Positive interaction between GPER and β-alanine in the dorsal root ganglion uncovers potential mechanisms: mediating continuous neuronal sensitization and neuroinflammation responses in neuropathic pain.
Journal of neuroinflammation
BACKGROUND:The pathogenesis of neuropathic pain and the reasons for the prolonged unhealing remain unknown. Increasing evidence suggests that sex oestrogen differences play a role in pain sensitivity, but few studies have focused on the oestrogen receptor which may be an important molecular component contributing to peripheral pain transduction. We aimed to investigate the impact of oestrogen receptors on the nociceptive neuronal response in the dorsal root ganglion (DRG) and spinal dorsal horn using a spared nerve injury (SNI) rat model of chronic pain. METHODS:We intrathecally (i.t.) administered a class of oestrogen receptor antagonists and agonists intrathecal (i.t.) administrated to male rats with SNI or normal rats to identify the main receptor. Moreover, we assessed genes identified through genomic metabolic analysis to determine the key metabolism point and elucidate potential mechanisms mediating continuous neuronal sensitization and neuroinflammatory responses in neuropathic pain. The excitability of DRG neurons was detected using the patch-clamp technique. Primary culture was used to extract microglia and DRG neurons, and siRNA transfection was used to silence receptor protein expression. Immunofluorescence, Western blotting, RT-PCR and behavioural testing were used to assess the expression, cellular distribution, and actions of the main receptor and its related signalling molecules. RESULTS:Increasing the expression and function of G protein-coupled oestrogen receptor (GPER), but not oestrogen receptor-α (ERα) and oestrogen receptor-β (ERβ), in the DRG neuron and microglia, but not the dorsal spinal cord, contributed to SNI-induced neuronal sensitization. Inhibiting GPER expression in the DRG alleviated SNI-induced pain behaviours and neuroinflammation by simultaneously downregulating iNOS, IL-1β and IL-6 expression and restoring GABAα2 expression. Additionally, the positive interaction between GPER and β-alanine and subsequent β-alanine accumulation enhances pain sensation and promotes chronic pain development. CONCLUSION:GPER activation in the DRG induces a positive association between β-alanine with iNOS, IL-1β and IL-6 expression and represses GABAα2 involved in post-SNI neuropathic pain development. Blocking GPER and eliminating β-alanine in the DRG neurons and microglia may prevent neuropathic pain development.
10.1186/s12974-022-02524-9
Down-regulation miR-146a-5p in Schwann cell-derived exosomes induced macrophage M1 polarization by impairing the inhibition on TRAF6/NF-κB pathway after peripheral nerve injury.
Experimental neurology
BACKGROUND:Both Schwann cell-derived exosomes (SC-Exos) and macrophagic sub-phenotypes are closely related to the regeneration and repair after peripheral nerve injury (PNI). However, the crosstalk between them is less clear. OBJECTIVE:We aim to investigate the roles and underlying mechanisms of exosomes from normoxia-condition Schwann cell (Nor-SC-Exos) and from post-injury oxygen-glucose-deprivation-condition Schwann cell in regulating macrophagic sub-phenotypes and peripheral nerve injury repair. METHOD:Both Nor-SC-Exos and OGD-SC-Exos were extracted through ultracentrifugation, identified by transmission electron microscopy (TEM), Nanosight tracking analysis (NTA) and western blotting. High-throughput sequencing was performed to explore the differential expression of microRNAs in both SC-Exos. In vitro, RAW264.7 macrophage was treated with two types of SC-Exos, M1 macrophagic markers (IL-10, Arg-1, TGF-β1) and M2 macrophagic markers (IL-6, IL-1β, TNF-α) were detected by enzyme-linked Immunosorbent Assay (ELISA) or qRT-PCR, and the expression of CD206, iNOS were detected via cellular immunofluorescence (IF) to judge macrophage sub-phenotypes. Dorsal root ganglion neurons (DRGns) were co-cultured with RAW264.7 cells treated with Nor-SC-Exos and OGD-SC-Exos, respectively, to explore their effect on neuron growth. In vivo, we established a sciatic nerve crush injury rat model. Nor-SC-Exos and OGD-SC-Exos were locally injected into the injury site. The mRNA expression of M1 macrophagic markers (IL-10, Arg-1, TGF-β1) and M2 macrophagic markers (IL-6, IL-1β, TNF-α) were detected by qRT-PCR to determine the sub-phenotype of macrophages in the injury site. IF was used to detect the expression of MBP and NF200, reflecting the myelin sheath and axon regeneration, and sciatic nerve function index (SFI) was measured to evaluate function repair. RESULT:In vitro, Nor-SC-Exos promoted macrophage M2 polarization, increased anti-inflammation factors secretion, and facilitated axon elongation of DRGns. OGD-SC-Exos promoted M1 polarization, increased pro-inflammation factors secretion, and restrained axon elongation of DRGns. High-throughput sequencing and qRT-PCR results found that compared with Nor-SC-Exos, a shift from anti-inflammatory (pro-M2) to pro-inflammatory (pro-M1) of OGD-SC-Exos was closely related to the down-regulation of miR-146a-5p and its decreasing inhibition on TRAF6/NF-κB pathway after OGD injury. In vivo, we found Nor-SC-Exos and miR-146a-5p mimic promoted regeneration of myelin sheath and axon, and facilitated sciatic function repair via targeting TRAF6, while OGD-SC-Exos and miR-146a-5p inhibitor restrained them. CONCLUSION:Our study confirmed that miR-146a-5p was significantly decreased in SC-Exos under the ischemia-hypoxic microenvironment of the injury site after PNI, which mediated its shift from promoting macrophage M2 polarization (anti-inflammation) to promoting M1 polarization (pro-inflammation), thereby limiting axonal regeneration and functional recovery.
10.1016/j.expneurol.2022.114295
Rejuvenating fecal microbiota transplant enhances peripheral nerve repair in aged mice by modulating endoneurial inflammation.
Experimental neurology
Peripheral nerve injury (PNI) resulting from trauma or neuropathies can cause significant disability, and its prognosis deteriorates with age. Emerging evidence suggests that gut dysbiosis and reduced fecal short-chain fatty acids (SCFAs) contribute to an age-related systemic hyperinflammation (inflammaging), which hinders nerve recovery after injury. This study thus aimed to evaluate the pro-regenerative effects of a rejuvenating fecal microbiota transplant (FMT) in a preclinical PNI model using aged mice. Aged C57BL/6 mice underwent bilateral crush injuries to their sciatic nerves. Subsequently, they either received FMT from young donors at three and four days after the injury or retained their aged gut microbiota. We analyzed gut microbiome composition and SCFA concentrations in fecal samples. The integrity of the ileac mucosal barrier was assessed by immunofluorescence staining of Claudin-1. Flow cytometry was utilized to examine immune cells and cytokine production in the ileum, spleen, and sciatic nerve. Various assessments, including behavioural tests, electrophysiological studies, and morphometrical analyses, were conducted to evaluate peripheral nerve function and repair following injury. Rejuvenating FMT reversed age-related gut dysbiosis by increasing Actinobacteria, especially Bifidobacteriales genera. This intervention also led to an elevation of gut SCFA levels and mitigated age-related ileac mucosal leakiness in aged recipients. Additionally, it augmented the number of T-helper 2 (Th2) and regulatory T (Treg) cells in the ileum and spleen, with the majority being positive for anti-inflammatory interleukin-10 (IL-10). In sciatic nerves, rejuvenating FMT resulted in increased M2 macrophage counts and a higher IL-10 production by IL-10TNF-α M2 macrophage subsets. Ultimately, restoring a youthful gut microbiome in aged mice led to improved nerve repair and enhanced functional recovery after PNI. Considering that FMT is already a clinically available technique, exploring novel translational strategies targeting the gut microbiome to enhance nerve repair in the elderly seems promising and warrants further evaluation.
10.1016/j.expneurol.2024.114774
Interleukin-10 signaling in somatosensory neurons controls CCL2 release and inflammatory response.
Brain, behavior, and immunity
Appropriate regulation of the inflammatory response is essential for survival. Interleukin-10 (IL-10), a well-known anti-inflammatory cytokine, plays a major role in controlling inflammation. In addition to immune cells, we previously demonstrated that the IL-10 receptor (IL-10R1) is expressed in dorsal root ganglion sensory neurons. There is emerging evidence that these sensory neurons contribute to immunoregulation, and we hypothesized that IL-10 signaling in dorsal root ganglion (DRG) neurons facilitates the regulation of the inflammatory response. We showed that mice that lack IL-10R1 specifically on advillin-positive neurons have exaggerated blood nitric oxide levels, spinal microglia activation, and cytokine upregulation in the spinal cord, liver, and gut compared to wild-type (WT) counterparts in response to systemic lipopolysaccharide (LPS) injection. Lack of IL-10R1 in DRG and trigeminal ganglion (TG) neurons also increased circulating and DRG levels of proinflammatory C-C motif chemokine ligand 2 (CCL2). Interestingly, analysis of published scRNA-seq data revealed that Ccl2 and Il10ra are expressed by similar types of DRG neurons; nonpeptidergic P2X purinoceptor (P2X3R + ) neurons. In primary cultures of DRG neurons, we demonstrated that IL-10R1 inhibits the production of CCL2, but not that of the neuropeptides substance P and calcitonin-gene related peptide (CGRP). Furthermore, our data indicate that ablation of Transient receptor potential vanilloid (TRPV)1 + neurons does not impact the regulation of CCL2 production by IL-10. In conclusion, we showed that IL-10 binds to its receptor on sensory neurons to downregulate CCL2 and contribute to immunoregulation by reducing the attraction of immune cells by DRG neuron-derived CCL2. This is the first evidence that anti-inflammatory cytokines limit inflammation through direct binding to receptors on sensory neurons. Our data also add to the growing literature that sensory neurons have immunomodulatory functions.
10.1016/j.bbi.2023.12.013
Role of IL-10 in Resolution of Inflammation and Functional Recovery after Peripheral Nerve Injury.
Siqueira Mietto Bruno,Kroner Antje,Girolami Elizabeth I,Santos-Nogueira Eva,Zhang Ji,David Samuel
The Journal of neuroscience : the official journal of the Society for Neuroscience
A rapid proinflammatory response after peripheral nerve injury is required for clearance of tissue debris (Wallerian degeneration) and effective regeneration. Unlike the CNS, this response is rapidly terminated in peripheral nerves starting between 2 and 3 weeks after crush injury. We examined the expression and role of the anti-inflammatory cytokine IL-10 in the resolution of inflammation and regeneration after sciatic nerve crush injury in mice. IL-10 mRNA increased over the first 7 d after injury, whereas at the protein level, immunofluorescence labeling showed IL-10(+) cells increased almost 3-fold in the first 3 weeks, with macrophages being the major cell type expressing IL-10. The role of IL-10 in nerve injury was assessed using IL-10-null mice. Increased numbers of macrophages were found in the distal segment of IL-10-null mice at early (3 d) and late (14 and 21 d) time points, suggesting that IL-10 may play a role in controlling the early influx and the later efflux of macrophages out of the nerve. A chemokine/cytokine PCR array of the nerve 24 h after crush showed a 2- to 4-fold increase in the expression of 10 proinflammatory mediators in IL-10(-/-) mice. In addition, myelin phagocytosis in vitro by LPS stimulated bone-marrow-derived macrophages from IL-10-null mice failed to downregulate expression of proinflammatory chemokines/cytokines, suggesting that IL-10 is required for the myelin-phagocytosis-induced shift of macrophages from proinflammatory to anti-inflammatory/pro-repair phenotype. The failure to switch off inflammation in IL-10-null mice was accompanied by impaired axon regeneration and poor recovery of motor and sensory function. SIGNIFICANCE STATEMENT:An appropriately regulated inflammatory response after peripheral nerve injury is essential for axon regeneration and recovery. The aim of this study was to investigate the expression and role of the anti-inflammatory cytokine IL-10 in terminating inflammation after sciatic nerve crush injury and promoting regeneration. IL-10 is rapidly expressed by macrophages after crush injury. Its role was assessed using IL-10-null mice, which showed that IL-10 plays a role in controlling the early influx and the later efflux of macrophages out of the injured nerve, reduces the expression of proinflammatory chemokines and cytokines, and is required for myelin-phagocytosis-induced shift of macrophages from proinflammatory to anti-inflammatory. Furthermore, lack of IL-10 leads to impaired axon regeneration and poor recovery of motor and sensory function.
10.1523/JNEUROSCI.2119-15.2015
In Situ Deactivation of Interleukin-6 Enhances Early Peripheral Nerve Regeneration in a Murine Injury Model.
Koulaxouzidis Georgios,Reim Gernot,Fluhr Joachim W,Simunovic Filip,Stark G Bjoern,Witzel Christian
Journal of reconstructive microsurgery
BACKGROUND:Systemic alteration of interleukin-6 (IL-6) influences peripheral nerve regeneration. We investigated the potential influences of in situ (at the coaptation site) IL-6 modulation in a peripheral-nerve-transection/sciatic-nerve-graft in vivo model. METHODS:We quantified the elongation of regenerating axons, the number of arborizing axons, and the number of branches per arborizing axon 7 days after the injury in mice expressing axonal fluorescent proteins (thy-1-YFP mice). Sciatic nerves from nonexpressing mice (C57Bl6 or IL-6(-/-) mice) were grafted into those expressing yellow fluorescent protein. We altered the in situ IL-6 concentration by loading a topical gelatin sponge with an inhibiting IL-6 receptor antibody or IL-6 combined with a soluble IL-6 receptor. Sciatic nerves from IL-6(-/-) mice were grafted into an additional group. The contralateral sham-operated side served as control in all the groups. RESULTS:Axonal elongation increased significantly with the in situ application of the IL-6 receptor antibody, while topical IL-6 significantly reduced the regeneration distance. The number of arborizing axons increased significantly in nerves grafted from IL-6(-/-) mice, whereas branches per arborizing axons remained stable. CONCLUSION:In situ IL-6 receptor inhibition and IL-6(-/-) nerve grafting enhance early peripheral nerve regeneration in an acute murine injury model.
10.1055/s-0035-1555114
Red nucleus IL-6 mediates the maintenance of neuropathic pain by inducing the productions of TNF-α and IL-1β through the JAK2/STAT3 and ERK signaling pathways.
Yang Qing-Qing,Li Hao-Nan,Zhang Shu-Ting,Yu Yan-Li,Wei Wei,Zhang Xi,Wang Jun-Yang,Zeng Xiao-Yan
Neuropathology : official journal of the Japanese Society of Neuropathology
We previously reported that interleukin (IL)-6 in the red nucleus (RN) is involved in the maintenance of neuropathic pain induced by spared nerve injury (SNI), and exerts a facilitatory effect via Janus-activated kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) and extracellular signal-regulated kinase (ERK) signal transduction pathways. The present study aimed at investigating the roles of tumor necrosis factor-α (TNF-α) and IL-1β in RN IL-6-mediated maintenance of neuropathic pain and related signal transduction pathways. Being similar to the elevation of RN IL-6 three weeks after SNI, increased protein levels of both TNF-α and IL-1β were also observed in the contralateral RN three weeks after the nerve injury. The upregulations of TNF-α and IL-1β were closely correlative with IL-6 and suppressed by intrarubral injection of a neutralizing antibody against IL-6. Administration of either the JAK2 antagonist AG490 or the ERK antagonist PD98059 to the RN of rats with SNI remarkably increased the paw withdrawal threshold (PWT) and inhibited the up-regulations of local TNF-α and IL-1β. Further experiments indicated that intrarubral injection of exogenous IL-6 in naive rats apparently lowered the PWT of the contralateral hindpaw and boosted the local expressions of TNF-α and IL-1β. Pretreatment with AG490 could block IL-6-induced tactile hypersensitivity and suppress the up-regulations of both TNF-α and IL-1β. However, injection of PD98059 in advance only inhibited the upregulation of IL-1β, but not TNF-α. These findings indicate that RN IL-6 mediates the maintenance of neuropathic pain by inducing the productions of TNF-α and IL-1β. IL-6 induces the expression of TNF-α through the JAK2/STAT3 pathway, and the production of IL-1β through the JAK2/STAT3 and ERK pathways.
10.1111/neup.12653
Increase of interleukin-6 mRNA in the spinal cord following peripheral nerve injury in the rat: potential role of IL-6 in neuropathic pain.
Arruda J L,Colburn R W,Rickman A J,Rutkowski M D,DeLeo J A
Brain research. Molecular brain research
Interleukin-6 (IL-6) is a multifunctional cytokine whose actions include modulation of proliferation, differentiation, and maturation of hemapoietic progenitors and other cell lineages; growth regulation of certain carcinoma cell lines; and control of cellular metabolic activities. Initially described in terms of its activities in the immune system and inflammation, accumulating evidence supports an essential role of IL-6 in the development, differentiation, regeneration and degeneration of neurons in the peripheral and central nervous system. We have previously demonstrated that immunoreactive-like IL-6 protein is significantly elevated in the spinal cord in response to peripheral nerve injury that results in neuropathic pain behaviors in the rat. In the current study, our objective was to determine if the source of IL-6 protein was endogenous to the central nervous system by measuring any detectable increases in spinal IL-6 mRNA expression following established mononeuropathy procedures associated with neuropathic pain: spinal nerve cryoneurolysis (SPCN) or spinal nerve tight ligation (SPTL). Using in situ hybridization and a digoxigenin-labeled oligonucleotide, IL-6 mRNA in neurons was significantly elevated at 3 and 7 days post SPCN and 7 days post SPTL in both dorsal and ventral horns. The cellular localization of the IL-6 mRNA expression was predominately neuronal as confirmed by NeuN serial staining. For example, in the SPCN 7 day group, IL-6 mRNA cell profiles in the ipsilateral dorsal horn were significantly different from the normal group (38.7+/-12.8 vs. 4.89+/-1.6, p<0.001). These data demonstrate the central, spinal production of a proinflammatory cytokine in response to a peripheral nerve injury. In addition, these results add to the growing body of literature implicating these immune products, cytokines, as potential neuromodulators/neurotransmitters and provides further evidence for their role in the nociceptive processing which leads to chronic pain.
Accelerated Nerve Regeneration in Mice by upregulated expression of interleukin (IL) 6 and IL-6 receptor after trauma.
Hirota H,Kiyama H,Kishimoto T,Taga T
The Journal of experimental medicine
In this study we aimed to examine a role for interleukin 6 (IL-6) and its receptor (IL-6R) in peripheral nerve regeneration in vivo. We first observed that cultured mouse embryonic dorsal root ganglia exhibited dramatic neurite extension by simultaneous addition of IL-6 and soluble IL-6R (sIL-6R), a complex that is known to interact with and activate a signal transducing receptor component, gp130. After injury in the hypoglossal nerve in adult mice by ligation, immunoreactivity to IL-6 was upregulated in Schwann cells at the lesional site as well as in the cell bodies of hypoglossal neurons in the brain stem. In the latter, upregulation of the immunoreactivity to IL-6R was also observed. Regeneration of axotomized hypoglossal nerve in vivo was significantly retarded by the administration of anti-IL-6R antibody. Surprisingly, accelerated regeneration of the axotomized nerve was achieved in transgenic mice constitutively expressing both IL-6 and IL-6R, as compared with nontransgenic controls. These results suggest that the IL-6 signal may play an important role in nerve regeneration after trauma in vivo.
10.1084/jem.183.6.2627
The role of interleukin-6 signaling in nervous tissue.
Rothaug Michelle,Becker-Pauly Christoph,Rose-John Stefan
Biochimica et biophysica acta
The cytokine interleukin-6 (IL-6) plays a critical role in the pathogenesis of inflammatory disorders and in the physiological homeostasis of neural tissue. Profound neuropathological changes, such as multiple sclerosis (MS), Parkinson's and Alzheimer's disease are associated with increased IL-6 expression in brain. Increased nocturnal concentrations of serum IL-6 are found in patients with impaired sleep whereas IL-6-deficient mice spend more time in rapid eye movement sleep associated with dreaming. IL-6 is crucial in the differentiation of oligodendrocytes, regeneration of peripheral nerves and acts as a neurotrophic factor. It exerts its cellular effects through two distinct pathways which include the anti-inflammatory pathway involving the membrane-bound IL-6 receptor (IL-6R) expressed on selective cells, including microglia, in a process known as classical signaling that is also critical for bacterial defense. In classical signaling binding of IL-6 to the membrane-bound IL-6R activates the β-receptor glycoprotein 130 (gp130) and subsequent down-stream signaling. The alternative, rather pro-inflammatory pathway, shown to mediate neurodegeneration in mice, termed trans-signaling, depends on a soluble form of the IL-6R that is capable of binding IL-6 to stimulate a response on distal cells that express gp130. A naturally occurring soluble form of gp130 (sgp130) has been identified that can specifically bind and neutralize the IL-6R/IL-6 complex. Thus, trans-signaling is blocked but classical signaling is completely unaffected. A modified, recombinant dimerized version of sgp130 (sgp130Fc) has successfully been used to block inflammatory processes in mice and may also be used in the clarification of IL-6 trans-signaling in neurological diseases.
10.1016/j.bbamcr.2016.03.018
The role of IL-6 and IL-1beta in painful perineural inflammatory neuritis.
Eliav Eli,Benoliel Rafael,Herzberg Uri,Kalladka Mythili,Tal Michael
Brain, behavior, and immunity
UNLABELLED:Inflammation along a nerve trunk (perineural inflammation), without detectable axonal damage, has been shown to induce transient pain in the organ supplied by the nerve. The aims of the present study were to study the role IL-6 and IL-1beta, in pain induced by perineural inflammation. METHODS:IL-6 and IL-1beta secretion from rat's sciatic nerves, L-5 Dorsal Root Ganglia (DRG), and the hind paw skin, 3 and 8 days following exposure of the nerve to Complete Freund's Adjuvant (CFA), were measured using ELISA method. Hind paw tactile-allodynia, mechano-hyperalgesia, heat-allodynia and electrical detection thresholds were tested up to 8 days following the application of CFA, IL-6 or IL-1beta adjacent to the sciatic nerve trunk. Employing electrophysiological recording, saphenous nerve spontaneous activity, nerve trunk mechano-sensitivity and paw tactile detection threshold (determined by recording action potential induced by the lowest mechanical stimulus) were assessed 3 and 8 days following exposure of the nerve trunk to CFA, IL-6, or IL-1beta. RESULTS:IL-6 and IL-1beta secretion from the nerve was significantly elevated on the 3rd day post-operation (DPO). On the 8th DPO, IL-6 levels returned to baseline while IL-1beta levels remained significantly elevated. The DRG cytokine's level was increased on the 3rd and 8th DPOs, contralateral cytokine's level was increased on the 3rd DPO. The skin IL-6 level was increased bilaterally on the 3rd DPO and returned to baseline on the 8th DPO. IL-1beta levels increased in the affected side on the 3rd and bilaterally on the 8th DPO. Direct application of IL-6 or CFA on the sciatic nerve induced significant hind paw tactile-allodynia from the 1st to 5th DPOs, reduced electrical detection threshold from the 1st to 3rd DPOs, mechano-hyperalgesia from 3rd to 5th DPOs and heat-allodynia on the 3rd DPO. Direct application of IL-1beta induced paw tactile and heat-allodynia on the 7-8th DPOs and mechano-hyperalgesia on the 5-8th DPOs. Perineural inflammation significantly increased spontaneous activity myelinated fibres 3 and 8 days following the application. Direct application of IL-6 induced elevation of spontaneous activity on the 3rd while IL-1beta on the 8th DPO. Nerve mechano-sensitivity was significantly increased on the 3rd day following exposure to CFA and IL-6 and on the 8th following CFA application. The rat's paw lowest mechanical force necessary for induction of action potential, was significantly reduced 3 days following CFA application. CONCLUSION:IL-6 and IL-1beta play an important role in pain induced by perineural inflammation. IL-6 activity is more prominent immediately following application (2-5th DPOs), while IL-1beta, activity is more significant in a later stage (5-8th DPOs).
10.1016/j.bbi.2009.01.012
Peripheral nerve fibroblasts as a source of IL-6, TNFalpha and IL-1 and their modulation by IFNgamma.
Murwani R,Armati P
Journal of the neurological sciences
Interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha), and interleukin-1 (IL-1) are immunomodulatory cytokines produced by Schwann cells of the peripheral nervous system (PNS). Their upregulation has been associated with autoimmune inflammatory diseases of the PNS such as Guillain-Barré Syndrome (GBS) and Chronic Inflammatory Demyelinating Neuropathy (CIDP). We now report that PNS fibroblasts and a PNS fibroblast cell line - MA-1 express mRNA for IL-6, TNFalpha and IL-I and that the MA-1 cell line secretes these molecules. Flow cytometry and fluorescent activated cell sorting defined that 76% of MA-1 fibroblasts were Thy1.1+ and 24% were Thy1.1-. Each subset expressed major histocompatibility class (MHC) I molecules and intercellular adhesion molecule-1 (ICAM-1). IFNgamma stimulation induced the expression of MHC II molecules in Thy1.1+, but not Thy1.1(-) cells. All MA-1 cells expressed mRNA for IL-6, TNFalpha, and IL-1 plus or minus IFNgamma stimulation. IFNgamma stimulation significantly reduced the production of IL-6 but increased TNFalpha production. Direct in situ reverse-transcriptase polymerase chain reaction (RT-PCR) showed that IL-1 mRNA staining increased significantly following IFNgamma stimulation. These results provide evidence for the first time that not only Schwann cells, but also peripheral nerve fibroblasts are a source of immunomodulatory cytokines within the PNS and may contribute to inflammatory processes in PNS disease.
Interleukin-6 (IL-6): a possible neuromodulator induced by neuronal activity.
Jüttler Eric,Tarabin Victoria,Schwaninger Markus
The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry
IL-6 and its receptor(s) are found in the CNS in health and disease. Cellular sources are glial cells and neurons. Glial production of IL-6 has intensively been studied, but comparatively little is known about the induction of IL-6 in neurons. Emerging evidence suggests that IL-6 possesses neurotrophic properties. Recent data show that neuronal IL-6 expression is induced by excitatory amino acids or membrane depolarization. This implicates that IL-6 is produced not only under pathological conditions but may play a critical role as a physiological neuromodulator that is induced by neuronal activity and regulates brain functions. In the following article, the authors review the current data on IL-6 expression in neurons, with special reference to the induction of IL-6 by neuronal activity. They discuss its direct and indirect effects as a neuromodulator and speculate about the possible function of IL-6 as a physiological regulatory molecule and as a neuroprotective agent in brain pathology.
10.1177/1073858402008003012
Transcriptional Control of Peripheral Nerve Regeneration.
Molecular neurobiology
Transcription factors are master regulators of various cellular processes under diverse physiological and pathological conditions. Many transcription factors that are differentially expressed after injury to peripheral nerves play important roles in nerve regeneration. Considering that rapid and timely regrowth of injured axons is a prerequisite for successful target reinnervation, here, we compile transcription factors that mediates axon elongation, including axon growth suppressor Klf4 and axon growth promoters c-Myc, Sox11, STAT3, Atf3, c-Jun, Smad1, C/EBPδ, and p53. Besides neuronal changes, Schwann cell phenotype modulation is also critical for nerve regeneration. The activation of Schwann cells at early time points post injury provides a permissive microenvironment whereas the re-differentiation of Schwann cells at later time points supports myelin sheath formation. Hence, c-Jun and Sox2, two critical drivers for Schwann cell reprogramming, as well as Krox-20 and Sox10, two essential regulators of Schwann cell myelination, are reviewed. These transcription factors may serve as promising targets for promoting the functional recovery of injured peripheral nerves.
10.1007/s12035-022-03090-0
Management of Iatrogenic Nerve Injuries.
Pulos Nicholas,Shin Emily H,Spinner Robert J,Shin Alexander Y
The Journal of the American Academy of Orthopaedic Surgeons
Iatrogenic peripheral nerve injuries from orthopaedic surgery can occur via many scenarios, including direct injury to the nerve during surgery, indirect injury via retraction or compartment syndrome, and injury from nonsurgical treatments such as injections and splinting. Successful management of iatrogenic nerve injuries requires an accurate diagnosis and timely, appropriate treatment. All orthopaedic surgeons must understand the preclinical study of nerve injury and the evaluation and treatment options for iatrogenic nerve injuries. Although a sharply transected nerve can be repaired immediately in the operating room under direct visualization, many injuries are not appreciated until the postoperative period. Advances in diagnostic studies and nerve repair techniques, nerve grafting, and nerve transfers have improved our ability to identify and treat such injuries.
10.5435/JAAOS-D-18-00510
A Brief Review of In Vitro Models for Injury and Regeneration in the Peripheral Nervous System.
International journal of molecular sciences
Nerve axonal injury and associated cellular mechanisms leading to peripheral nerve damage are important topics of research necessary for reducing disability and enhancing quality of life. Model systems that mimic the biological changes that occur during human nerve injury are crucial for the identification of cellular responses, screening of novel therapeutic molecules, and design of neural regeneration strategies. In addition to in vivo and mathematical models, in vitro axonal injury models provide a simple, robust, and reductionist platform to partially understand nerve injury pathogenesis and regeneration. In recent years, there have been several advances related to in vitro techniques that focus on the utilization of custom-fabricated cell culture chambers, microfluidic chamber systems, and injury techniques such as laser ablation and axonal stretching. These developments seem to reflect a gradual and natural progression towards understanding molecular and signaling events at an individual axon and neuronal-soma level. In this review, we attempt to categorize and discuss various in vitro models of injury relevant to the peripheral nervous system and highlight their strengths, weaknesses, and opportunities. Such models will help to recreate the post-injury microenvironment and aid in the development of therapeutic strategies that can accelerate nerve repair.
10.3390/ijms23020816
Iron Metabolism and Ferroptosis in Peripheral Nerve Injury.
Oxidative medicine and cellular longevity
Peripheral nerve injury (PNI) is a major clinical problem that may lead to different levels of sensory and motor dysfunction including paralysis. Due to the high disability rate and unsatisfactory prognosis, the exploration and revealment of the mechanisms involved in the PNI are urgently required. Ferroptosis, a recently identified novel form of cell death, is an iron-dependent process. It is a unique modality of cell death, closely associated with iron concentrations, generation of reactive oxygen species, and accumulation of the lipid reactive oxygen species. These processes are regulated by multiple cellular metabolic pathways, including iron overloading, lipid peroxidation, and the glutathione/glutathione peroxidase 4 pathway. Furthermore, ferroptosis is accompanied by morphological changes in the mitochondria, such as increased membrane density and shrunken mitochondria; this association between ferroptosis and mitochondrial damage has been detected in various diseases, including spinal cord injury and PNI. The inhibition of ferroptosis can promote the repair of damaged peripheral nerves, reduce mitochondrial damage, and promote the recovery of neurological function. In this review, we intend to discuss the detailed mechanisms of ferroptosis and summarize the current researches on ferroptosis with respect to nerve injury. This review also aims at providing new insights on targeting ferroptosis for PNI treatment.
10.1155/2022/5918218
Induction of Autophagy and Its Role in Peripheral Nerve Regeneration after Peripheral Nerve Injury.
International journal of molecular sciences
No matter what treatment is used after nerve transection, a complete cure is impossible, so basic and clinical research is underway to find a cure. As part of this research, autophagy is being investigated for its role in nerve regeneration. Here, we review the existing literature regarding the involvement and significance of autophagy in peripheral nerve injury and regeneration. A comprehensive literature review was conducted to assess the induction and role of autophagy in peripheral nerve injury and subsequent regeneration. Studies were included if they were prospective or retrospective investigations of autophagy and facial or peripheral nerves. Articles not mentioning autophagy or the facial or peripheral nerves, review articles, off-topic articles, and those not written in English were excluded. A total of 14 peripheral nerve studies that met these criteria, including 11 involving sciatic nerves, 2 involving facial nerves, and 1 involving the inferior alveolar nerve, were included in this review. Studies conducted on rats and mice have demonstrated activation of autophagy and expression of related factors in peripheral nerves with or without stimulation of autophagy-inducing factors such as rapamycin, curcumin, three-dimensional melatonin nerve scaffolds, CXCL12, resveratrol, nerve growth factor, lentinan, adipose-derived stem cells and melatonin, basic fibroblast growth factor, and epothilone B. Among the most studied of these factors in relation to degeneration and regeneration of facial and sciatic nerves are LC3II/I, PI3K, mTOR, Beclin-1, ATG3, ATG5, ATG7, ATG9, and ATG12. This analysis indicates that autophagy is involved in the process of nerve regeneration following facial and sciatic nerve damage. Inadequate autophagy induction or failure of autophagy responses can result in regeneration issues after peripheral nerve damage. Animal studies suggest that autophagy plays an important role in peripheral nerve degeneration and regeneration.
10.3390/ijms242216219
Epigenetic and epitranscriptomic regulation of axon regeneration.
Molecular psychiatry
Effective axonal regeneration in the adult mammalian nervous system requires coordination of elevated intrinsic growth capacity and decreased responses to the inhibitory environment. Intrinsic regenerative capacity largely depends on the gene regulatory network and protein translation machinery. A failure to activate these pathways upon injury is underlying a lack of robust axon regeneration in the mature mammalian central nervous system. Epigenetics and epitranscriptomics are key regulatory mechanisms that shape gene expression and protein translation. Here, we provide an overview of different types of modifications on DNA, histones, and RNA, underpinning the regenerative competence of axons in the mature mammalian peripheral and central nervous systems. We highlight other non-neuronal cells and their epigenetic changes in determining the microenvironment for tissue repair and axon regeneration. We also address advancements of single-cell technology in charting transcriptomic and epigenetic landscapes that may further facilitate the mechanistic understanding of differential regenerative capacity in neuronal subtypes. Finally, as epigenetic and epitranscriptomic processes are commonly affected by brain injuries and psychiatric disorders, understanding their alterations upon brain injury would provide unprecedented mechanistic insights into etiology of injury-associated-psychiatric disorders and facilitate the development of therapeutic interventions to restore brain function.
10.1038/s41380-023-02028-9
Intrinsic mechanisms of neuronal axon regeneration.
Mahar Marcus,Cavalli Valeria
Nature reviews. Neuroscience
Permanent disabilities following CNS injuries result from the failure of injured axons to regenerate and rebuild functional connections with their original targets. By contrast, injury to peripheral nerves is followed by robust regeneration, which can lead to recovery of sensory and motor functions. This regenerative response requires the induction of widespread transcriptional and epigenetic changes in injured neurons. Considerable progress has been made in recent years in understanding how peripheral axon injury elicits these widespread changes through the coordinated actions of transcription factors, epigenetic modifiers and, to a lesser extent, microRNAs. Although many questions remain about the interplay between these mechanisms, these new findings provide important insights into the pivotal role of coordinated gene expression and chromatin remodelling in the neuronal response to injury.
10.1038/s41583-018-0001-8
When IL-17 gets on your nerves.
Cell
Microbiota-induced IL-17 production mediates CNS processes and animal behavior. However, its role on the peripheral nervous system (PNS) remains largely unknown. Enamorado et al. demonstrate that commensal-specific Th17 cells are recalled following tissue injury to support local nerve regeneration, a process orchestrated by IL-17 signaling on peripheral neurons.
10.1016/j.cell.2022.12.048
CNTF-STAT3-IL-6 Axis Mediates Neuroinflammatory Cascade across Schwann Cell-Neuron-Microglia.
Hu Zhongsheng,Deng Nan,Liu Kaili,Zhou Nan,Sun Yue,Zeng Wenwen
Cell reports
Neuroinflammation is a crucial mechanism in many neurological disorders. Injury to the peripheral sensory nerves leads to a neuroinflammatory response in the somatosensory pathway, from dorsal root ganglia (DRG) to the spinal cord, contributing to neuropathic pain. How the immune reaction is initiated peripherally and propagated to the spinal cord remains less clear. Here, we find that ciliary neurotrophic factor (CNTF), highly expressed in Schwann cells, mediates neuroinflammatory response through the activating signal transducer and activator of transcription 3 (STAT3) and inducing interleukin 6 (IL-6) in sensory neurons. Cntf deficiency attenuates neuroinflammation in DRG and the spinal cord with alleviated pain post-injury. Recombinant CNTF applied to the sensory nerves recapitulates neuroinflammation in the DRG and spinal cord, with consequent pain development. We delineate the CNTF-STAT3-IL-6 axis in mediating the onset and progression of the inflammatory cascade from the periphery to the spinal cord with therapeutic implications for neuropathic pain.
10.1016/j.celrep.2020.107657
Immunity to the microbiota promotes sensory neuron regeneration.
Cell
Tissue immunity and responses to injury depend on the coordinated action and communication among physiological systems. Here, we show that, upon injury, adaptive responses to the microbiota directly promote sensory neuron regeneration. At homeostasis, tissue-resident commensal-specific T cells colocalize with sensory nerve fibers within the dermis, express a transcriptional program associated with neuronal interaction and repair, and promote axon growth and local nerve regeneration following injury. Mechanistically, our data reveal that the cytokine interleukin-17A (IL-17A) released by commensal-specific Th17 cells upon injury directly signals to sensory neurons via IL-17 receptor A, the transcription of which is specifically upregulated in injured neurons. Collectively, our work reveals that in the context of tissue damage, preemptive immunity to the microbiota can rapidly bridge biological systems by directly promoting neuronal repair, while also identifying IL-17A as a major determinant of this fundamental process.
10.1016/j.cell.2022.12.037
Interleukin-17 contributes to neuroinflammation and neuropathic pain following peripheral nerve injury in mice.
Kim Cristina Fabiola,Moalem-Taylor Gila
The journal of pain : official journal of the American Pain Society
UNLABELLED:Cytokines, essential mediators of inflammatory and immune responses, play an important role in the pathophysiological processes associated with neuropathic pain following peripheral nerve injury. Recently, a novel proinflammatory cytokine, the interleukin (IL)-17, was found to orchestrate inflammatory responses in a wide range of inflammatory and autoimmune diseases of the nervous system. Here, we investigated the role of IL-17 in mediating neuroinflammation and pain hypersensitivity using the neuropathic pain model of partial ligation of the sciatic nerve in mice. Compared to wild-type, IL-17 knockout (KO) mice displayed significantly decreased mechanical pain hypersensitivity as well as decreased infiltration of T cells and macrophages to the injured sciatic nerves and the L3-L5 dorsal root ganglia and decreased activation of microglia and astrocytes in the L3-5 dorsal and ventral horns of the spinal cord. Further, intraplantar and intraneural injection of recombinant IL-17 into the hind paw and the sciatic nerve, respectively, induced both mechanical allodynia and thermal hyperalgesia, whereas intrathecal injection produced thermal hyperalgesia. IL-17 administration was associated with a significant increase in the numbers of infiltrating neutrophils and activated dendritic cells in the injected hind paws and infiltrating neutrophils in the injected sciatic nerves. Taken together, our results demonstrate that IL-17 contributes to the regulation of immune cell infiltration and glial activation after peripheral nerve injury and the ensuing neuropathic pain. PERSPECTIVE:IL-17 is an important regulator of immune responses and is involved in inducing and mediating proinflammatory reactions. Using IL-17 KO mice, we have demonstrated that IL-17 contributes to neuroinflammatory responses and pain hypersensitivity following neuropathic injury. This work identifies IL-17 as a potential therapeutic target in neuropathic pain.
10.1016/j.jpain.2010.08.003
Interleukin-1 beta promotes sensory nerve regeneration after sciatic nerve injury.
Temporin Ko,Tanaka Hiroyuki,Kuroda Yusuke,Okada Kiyoshi,Yachi Koji,Moritomo Hisao,Murase Tsuyoshi,Yoshikawa Hideki
Neuroscience letters
Nerve injury brings about axonal disconnection, and thus axonal extension is one of the important steps for nerve regeneration. Expression of the pro-inflammatory cytokine interleukin-1 beta (IL-1beta) is increased at the early stage of nervous system injury, and previously IL-1beta has been reported to promote neurite outgrowth by inhibiting RhoA activity in vitro. However, the effect of IL-1beta on axonal extension in vivo has not been obvious. Now we examine whether IL-1beta takes advantages on sciatic nerve regeneration. Sciatic nerves of rats are transected and sutured, and IL-1beta or PBS is locally administered for 2 weeks. Although IL-1beta does not influence on motor functional recovery, it promotes sensory functional recovery, estimated by toe pinch test, and increases the number and the area of neurofilament-positive axons at 12 weeks compared with PBS. Moreover IL-1beta, which promotes Schwann cell proliferation and thus may inhibit myelination, does not impair remyelination, estimated by myelin basic protein. These findings suggest that IL-1beta may contribute to sensory nerve regeneration following sciatic nerve injury by promoting axonal extension.
10.1016/j.neulet.2008.05.081
Spinal interleukin-24 contributes to neuropathic pain after peripheral nerve injury through interleukin-20 receptor2 in mice.
Experimental neurology
Neuroinflammation is critically involved in nerve injury-induced neuropathic pain, characterized by local and systemic increased levels of proinflammatory cytokines. Interleukin-24 (IL-24), a key member of the IL-10 family, has been extensively studied for its therapeutic potential in various diseases, including cancer, autoimmune disorders, and bacterial infections, but whether it is involved in the regulation of neuropathic pain caused by peripheral nerve injury (PNI) has not been well established. In this study, we reported that spared nerve injury (SNI) induced a significant upregulation of IL-24 in fibroblasts, neurons, and oligodendrocyte precursor cells (OPCs, also called NG2-glia) in the affected spinal dorsal horns (SDHs), as well as dorsal root ganglions (DRGs). We also found that tumor necrosis factor α (TNF-α) induced the transcriptional expression of IL-24 in cultured fibroblasts, neurons, and NG2-glia; in addition, astrocytes, microglia, and NG2-glia treated with TNF-α exhibited a prominent increase in interleukin-20 receptor 2 (IL-20R2) expression. Furthermore, we evaluated the ability of IL-24 and IL-20R2 to attenuate pain in preclinical models of neuropathic pain. Intrathecal (i.t.) injection of IL-24 neutralizing antibody or IL-20R2 neutralizing antibody could effectively alleviate mechanical allodynia and thermal hyperalgesia after PNI. Similarly, intrathecal injection of IL-24 siRNA or IL-20R2 siRNA also alleviated mechanical allodynia after SNI. The inhibition of IL-24 reduced SNI-induced proinflammatory cytokine (IL-1β and TNF-α) production and increased anti-inflammatory cytokine (IL-10) production. Meanwhile, the inhibition of IL-20R2 also decreased IL-1β mRNA expression after SNI. Collectively, our findings revealed that IL-24/IL-20R might contribute to neuropathic pain through inflammatory response. Therefore, targeting IL-24 could be a promising strategy for treating neuropathic pain induced by PNI.
10.1016/j.expneurol.2023.114643
Extracellular vesicles and their role in peripheral nerve regeneration.
Hercher David,Nguyen Mai Quyen,Dworak Helene
Experimental neurology
Peripheral nerve injuries often result in sensory and motor dysfunction in respective parts of the body. Regeneration after peripheral nerve injuries is a complex process including the differentiation of Schwann cells, recruiting of macrophages, blood vessel growth and axonal regrowth. Extracellular vesicles (EVs) are considered to play a pivotal role in intercellular communication and transfer of biological information. Specifically, their bioactivity and ability to deliver cargos of various types of nucleic acids and proteins have made them a potential vehicle for neurotherapeutics. However, production, characterization, dosage and targeted delivery of EVs still pose challenges for the clinical translation of EV therapeutics. This review summarizes the current knowledge of EVs in the context of the healthy and injured peripheral nerve and addresses novel concepts for modification of EVs as therapeutic agents for peripheral nerve regeneration.
10.1016/j.expneurol.2021.113968
Protease Activated Receptor 1 and Its Ligands as Main Regulators of the Regeneration of Peripheral Nerves.
Biomolecules
In contrast with the brain and spinal cord, peripheral nerves possess a striking ability to regenerate after damage. This characteristic of the peripheral nervous system is mainly due to a specific population of glial cells, the Schwann cells. Schwann cells promptly activate after nerve injury, dedifferentiate assuming a repair phenotype, and assist axon regrowth. In general, tissue injury determines the release of a variety of proteases which, in parallel with the degradation of their specific targets, also activate plasma membrane receptors known as protease-activated receptors (PARs). PAR1, the prototypical member of the PAR family, is also known as thrombin receptor and is present at the Schwann cell plasma membrane. This receptor is emerging as a possible regulator of the pro-regenerative capacity of Schwann cells. Here, we summarize the most recent literature data describing the possible contribution of PAR1 and PAR1-activating proteases in regulating the regeneration of peripheral nerves.
10.3390/biom11111668
Exercise, neurotrophins, and axon regeneration in the PNS.
English Arthur W,Wilhelm Jennifer C,Ward Patricia J
Physiology (Bethesda, Md.)
Electrical stimulation and exercise are treatments to enhance recovery from peripheral nerve injuries. Brain-derived neurotrophic factor and androgen receptor signaling are requirements for the effectiveness of these treatments. Increased neuronal activity is adequate to promote regeneration in injured nerves, but the dosing of activity and its relationship to neurotrophins and sex steroid hormones is less clear. Translation of these therapies will require principles associated with their cellular mechanisms.
10.1152/physiol.00028.2014
Neuregulin 1 role in Schwann cell regulation and potential applications to promote peripheral nerve regeneration.
Gambarotta Giovanna,Fregnan Federica,Gnavi Sara,Perroteau Isabelle
International review of neurobiology
Neuregulin 1 (NRG1) is a multifunctional and versatile protein: its numerous isoforms can signal in a paracrine, autocrine, or juxtacrine manner, playing a fundamental role during the development of the peripheral nervous system and during the process of nerve repair, suggesting that the treatment with NRG1 could improve functional outcome following injury. Accordingly, the use of NRG1 in vivo has already yielded encouraging results. The aim of this review is to focus on the role played by the different NRG1 isoforms during peripheral nerve regeneration and remyelination and to identify good candidates to be used for the development of tissue engineered medical devices delivering NRG1, with the objective of promoting better nerve repair.
10.1016/B978-0-12-410499-0.00009-5
Repurposing Small Molecules to Target PPAR-γ as New Therapies for Peripheral Nerve Injuries.
Rayner Melissa L D,Healy Jess,Phillips James B
Biomolecules
The slow rate of neuronal regeneration that follows peripheral nerve repair results in poor recovery, particularly where reinnervation of muscles is delayed, leading to atrophy and permanent loss of function. There is a clear clinical need to develop drug treatments that can accelerate nerve regeneration safely, restoring connections before the target tissues deteriorate irreversibly. The identification that the Rho/Rho-associated kinase (ROCK) pathway acts to limit neuronal growth rate is a promising advancement towards the development of drugs. Targeting Rho or ROCK directly can act to suppress the activity of this pathway; however, the pathway can also be modulated through the activation of upstream receptors; one of particular interest being peroxisome proliferator-activated receptor gamma (PPAR-γ). The connection between the PPAR-γ receptor and the Rho/ROCK pathway is the suppression of the conversion of inactive guanosine diphosphate (GDP)-Rho to active guanosine triphosphate GTP-Rho, resulting in the suppression of Rho/ROCK activity. PPAR-γ is known for its role in cellular metabolism that leads to cell growth and differentiation. However, more recently there has been a growing interest in targeting PPAR-γ in peripheral nerve injury (PNI). The localisation and expression of PPAR-γ in neural cells following a PNI has been reported and further in vitro and in vivo studies have shown that delivering PPAR-γ agonists following injury promotes nerve regeneration, leading to improvements in functional recovery. This review explores the potential of repurposing PPAR-γ agonists to treat PNI and their prospective translation to the clinic.
10.3390/biom11091301
[Research progress of adipose-derived stem cells in promoting the repair of peripheral nerve injury].
Zhongguo xiu fu chong jian wai ke za zhi = Zhongguo xiufu chongjian waike zazhi = Chinese journal of reparative and reconstructive surgery
OBJECTIVE:To summarize the research progress of adipose-derived stem cells (ADSCs) in promoting the repair of peripheral nerve injury. METHODS:The related literature at home and abroad in recent years was widely reviewed, the mechanism of ADSCs promoting the repair of peripheral nerve injury was introduced, and its basic research progress was analyzed and summarized. Finally, the clinical transformation application of ADSCs in the treatment of peripheral nerve injury was introduced, the existing problems were pointed out, and the new treatment regimen was prospected. RESULTS:ADSCs have the function of differentiation and paracrine, and their secreted neurotrophic factors, antiapoptosis, and antioxidant factors can promote the repair of peripheral nerve injury. CONCLUSION:ADSCs are rich in content and easy to obtain, which has a definite effectiveness on the repair of peripheral nerve injury with potential clinical prospect.
10.7507/1002-1892.201910009
Neuregulin/ErbB Signaling in Developmental Myelin Formation and Nerve Repair.
Birchmeier Carmen,Bennett David L H
Current topics in developmental biology
Myelin is essential for rapid and accurate conduction of electrical impulses by axons in the central and peripheral nervous system (PNS). Myelin is formed in the early postnatal period, and developmental myelination in the PNS depends on axonal signals provided by Nrg1/ErbB receptors. In addition, Nrg1 is required for effective nerve repair and remyelination in adulthood. We discuss here similarities and differences in Nrg1/ErbB functions in developmental myelination and remyelination after nerve injury.
10.1016/bs.ctdb.2015.11.009
Natural polysaccharides and their derivatives as potential medical materials and drug delivery systems for the treatment of peripheral nerve injuries.
Carbohydrate polymers
Peripheral nerve repair following injury is one of the most serious problems in neurosurgery. Clinical outcomes are often unsatisfactory and associated with a huge socioeconomic burden. Several studies have revealed the great potential of biodegradable polysaccharides for improving nerve regeneration. We review here the promising therapeutic strategies involving different types of polysaccharides and their bio-active composites for promoting nerve regeneration. Within this context, polysaccharide materials widely used for nerve repair in different forms are highlighted, including nerve guidance conduits, hydrogels, nanofibers and films. While nerve guidance conduits and hydrogels were used as main structural scaffolds, the other forms including nanofibers and films were generally used as additional supporting materials. We also discuss the issues of ease of therapeutic implementation, drug release properties and therapeutic outcomes, together with potential future directions of research.
10.1016/j.carbpol.2023.120934
Recent Findings on the Effects of Pharmacological Agents on the Nerve Regeneration after Peripheral Nerve Injury.
Bolandghamat Samira,Behnam-Rassouli Morteza
Current neuropharmacology
Peripheral nerve injuries (PNIs) are accompanied with neuropathic pain and functional disability. Despite improvements in surgical repair techniques in recent years, the functional recovery is yet unsatisfied. Indeed a successful nerve repair depends not only on the surgical strategy but also on the cellular and molecular mechanisms involved in traumatic nerve injury. In contrast to all strategies suggested for nerve repair, pharmacotherapy is a cheap, accessible and non-invasive treatment that can be used immediately after nerve injury. This study aimed to review the effects of some pharmacological agents on the nerve regeneration after traumatic PNI evaluated by functional, histological and electrophysiological assessments. In addition, some cellular and molecular mechanisms responsible for their therapeutic actions, restricted to neural tissue, are suggested. These findings can not only help to find better strategies for peripheral nerve repair, but also to identify the neuropathic effects of various medications and their mechanisms of action.
10.2174/1570159X18666200507084024
Migrating Schwann cells direct axon regeneration within the peripheral nerve bridge.
Min Qing,Parkinson David B,Dun Xin-Peng
Glia
Schwann cells within the peripheral nervous system possess a remarkable regenerative potential. Current research shows that peripheral nerve-associated Schwann cells possess the capacity to promote repair of multiple tissues including peripheral nerve gap bridging, skin wound healing, digit tip repair as well as tooth regeneration. One of the key features of the specialized repair Schwann cells is that they become highly motile. They not only migrate into the area of damaged tissue and become a key component of regenerating tissue but also secrete signaling molecules to attract macrophages, support neuronal survival, promote axonal regrowth, activate local mesenchymal stem cells, and interact with other cell types. Currently, the importance of migratory Schwann cells in tissue regeneration is most evident in the case of a peripheral nerve transection injury. Following nerve transection, Schwann cells from both proximal and distal nerve stumps migrate into the nerve bridge and form Schwann cell cords to guide axon regeneration. The formation of Schwann cell cords in the nerve bridge is key to successful peripheral nerve repair following transection injury. In this review, we first examine nerve bridge formation and the behavior of Schwann cell migration in the nerve bridge, and then discuss how migrating Schwann cells direct regenerating axons into the distal nerve. We also review the current understanding of signals that could activate Schwann cell migration and signals that Schwann cells utilize to direct axon regeneration. Understanding the molecular mechanism of Schwann cell migration could potentially offer new therapeutic strategies for peripheral nerve repair.
10.1002/glia.23892
Macrophage biology in the peripheral nervous system after injury.
Progress in neurobiology
Neuroinflammation has positive and negative effects. This review focuses on the roles of macrophage in the PNS. Transection of PNS axons leads to degeneration and clearance of the distal nerve and to changes in the region of the axotomized cell bodies. In both locations, resident and infiltrating macrophages are found. Macrophages enter these areas in response to expression of the chemokine CCL2 acting on the macrophage receptor CCR2. In the distal nerve, macrophages and other phagocytes are involved in clearance of axonal debris, which removes molecules that inhibit nerve regeneration. In the cell body region, macrophage trigger the conditioning lesion response, a process in which neurons increase their regeneration after a prior lesion. In mice in which the genes for CCL2 or CCR2 are deleted, neither macrophage infiltration nor the conditioning lesion response occurs in dorsal root ganglia (DRG). Macrophages exist in different phenotypes depending on their environment. These phenotypes have different effects on axonal clearance and neurite outgrowth. The mechanism by which macrophages affect neuronal cell bodies is still under study. Overexpression of CCL2 in DRG in uninjured animals leads to macrophage accumulation in the ganglia and to an increase in the growth potential of DRG neurons. This increased growth requires activation of neuronal STAT3. In contrast, in acute demyelinating neuropathies, macrophages are involved in stripping myelin from peripheral axons. The molecular mechanisms that trigger macrophage action after trauma and in autoimmune disease are receiving increased attention and should lead to avenues to promote regeneration and protect axonal integrity.
10.1016/j.pneurobio.2018.12.001
IL-27 Counteracts Neuropathic Pain Development Through Induction of IL-10.
Fonseca Miriam M,Davoli-Ferreira Marcela,Santa-Cecília Flávia,Guimarães Rafaela M,Oliveira Francisco F B,Kusuda Ricardo,Ferreira David W,Alves-Filho José C,Cunha Fernando Q,Cunha Thiago M
Frontiers in immunology
Neuroimmune-glia interactions have been implicated in the development of neuropathic pain. Interleukin-27 (IL-27) is a cytokine that presents regulatory activity in inflammatory conditions of the central nervous system. Thus, we hypothesized that IL-27 would participate in the neuropathic pain process. Here, we found that neuropathic pain caused by peripheral nerve injury (spared nerve injury model; SNI), was enhanced in IL-27-deficient mice, whereas nociceptive pain is similar to that of wild-type mice. SNI induced an increase in the expression of IL-27 and its receptor subunit () in the sensory ganglia and spinal cord. IL-27 receptor was expressed mainly in resident macrophage, microglia, and astrocytes of the sensory ganglia and spinal cord, respectively. Finally, we identify that the antinociceptive effect of IL-27 was not observed in IL-10 mice. These results provided evidence that IL-27 is a cytokine produced after peripheral nerve injury that counteracts neuropathic pain development through induction of the antinociceptive cytokine IL-10. In summary, our study unraveled the role of IL-27 as a regulatory cytokine that counteracts the development of neuropathic pain after peripheral nerve damage. In conclusion, they indicate that immunotherapies based on IL-27 could emerge as possible therapeutic approaches for the prevention of neuropathic pain development after peripheral nerve injury.
10.3389/fimmu.2019.03059
IL-10 and IL-1β mediate neuropathic-pain like behavior in the ventrolateral orbital cortex.
Shao Qingdong,Li Yufei,Wang Qiang,Zhao Jianning
Neurochemical research
Previous evidence has shown that the glial cells can be activated by peripheral nerve injury and release both pro-inflammatory and anti-inflammatory cytokines, which play crucial roles in the establishment and maintenance of neuropathic pain. The present study examined the roles of anti-inflammatory cytokine IL-10 and pro-inflammatory IL-1β on allodynia induced by spared nerve injury (SNI) in the ventrolateral orbital cortex (VLO) in the rat. The mechanical paw withdrawal threshold (PWT) was measured using von-Frey filaments. Microinjection of IL-10 (0.1, 0.5, 1 μg/0.5 μl) into the VLO, contralateral to the site of nerve injury attenuated allodynia; PWT increased in a dose-dependent manner. Similar to IL-10, administration of rabbit anti-rat IL-1β antibody (0.1, 1.0 and 10 ng/0.5 μl) into the same VLO site also alleviated allodynia with a dose-dependent fashion. Moreover, western blotting results showed expression levels of IL-10 and IL-1β significantly up-regulated in the contralateral VLO of SNI rats as compared with that of sham-operated rats. These results suggest that anti-inflammatory cytokine IL-10 and pro-inflammatory cytokine IL-1β mediate neuropathic-pain like behavior at the cerebral cortex level; IL-10 released from activated glial cells in the VLO can potentially attenuate allodynia while IL-1β released from activated glial cells in the VLO can potentially maintain or facilitate allodynia. These results provide new insights and site for therapy at the cerebral cortex level in neuropathic pain condition.
10.1007/s11064-015-1521-5
CD4+ T cell expression of the IL-10 receptor is necessary for facial motoneuron survival after axotomy.
Runge Elizabeth M,Iyer Abhirami K,Setter Deborah O,Kennedy Felicia M,Sanders Virginia M,Jones Kathryn J
Journal of neuroinflammation
BACKGROUND:After peripheral nerve transection, facial motoneuron (FMN) survival depends on an intact CD4+ T cell population and a central source of interleukin-10 (IL-10). However, it has not been determined previously whether CD4+ T cells participate in the central neuroprotective IL-10 cascade after facial nerve axotomy (FNA). METHODS:Immunohistochemical labeling of CD4+ T cells, pontine vasculature, and central microglia was used to determine whether CD4+ T cells cross the blood-brain barrier and enter the facial motor nucleus (FMNuc) after FNA. The importance of IL-10 signaling in CD4+ T cells was assessed by performing adoptive transfer of IL-10 receptor beta (IL-10RB)-deficient CD4+ T cells into immunodeficient mice prior to injury. Histology and qPCR were utilized to determine the impact of IL-10RB-deficient T cells on FMN survival and central gene expression after FNA. Flow cytometry was used to determine whether IL-10 signaling in T cells was necessary for their differentiation into neuroprotective subsets. RESULTS:CD4+ T cells were capable of crossing the blood-brain barrier and associating with reactive microglial nodules in the axotomized FMNuc. Full induction of central IL-10R gene expression after FNA was dependent on CD4+ T cells, regardless of their own IL-10R signaling capability. Surprisingly, CD4+ T cells lacking IL-10RB were incapable of mediating neuroprotection after axotomy and promoted increased central expression of genes associated with microglial activation, antigen presentation, T cell co-stimulation, and complement deposition. There was reduced differentiation of IL-10RB-deficient CD4+ T cells into regulatory CD4+ T cells in vitro. CONCLUSIONS:These findings support the interdependence of IL-10- and CD4+ T cell-mediated mechanisms of neuroprotection after axotomy. CD4+ T cells may potentiate central responsiveness to IL-10, while IL-10 signaling within CD4+ T cells is necessary for their ability to rescue axotomized motoneuron survival. We propose that loss of IL-10 signaling in CD4+ T cells promotes non-neuroprotective autoimmunity after FNA.
10.1186/s12974-020-01772-x
The Preventive Effect of IL-1beta Antagonist on Diabetic Peripheral Neuropathy.
Hangping Zheng,Ling Han,Lijin Ji,Wenting Zhao,Xiaoxia Liu,Qi Zhang,Xiaoming Zhu,Qingchun Li,Yiming Li,Qian Xiong,Ji Hu,Bin Lu,Shuo Zhang
Endocrine, metabolic & immune disorders drug targets
OBJECTIVE:To investigate the relationship between Interleukin-1beta (IL-1beta) and diabetic peripheral neuropathy (DPN) using animal models. METHODS:The rat model of diabetic neuropathy was induced by intraperitoneal injection of a single dose of streptozotocin (STZ) at 65mg/kg. Diabetic rats were randomly divided into two groups (10 each), one treated with 0.9% saline (DMS group) and the other with interleukin-1 receptor antagonist (IL-1RA) at 50mg/kg (DMI group) twice a day for 5 weeks. Ten normal rats matched for weight, age and sex served as normal controls (Con group) and were treated with saline. Morphologic studies of sciatic nerves were achieved using light and transmission electron microscopy. RESULTS:Transmission electron microscopy of the sciatic nerve showed the ultrastructure of myelin and the axon in the IL-1RA group was highly protected compared to diabetic controls. CONCLUSION:High levels of circulating IL-1beta may be associated with the risk of DPN and anti-IL-1 treatment may provide a potential strategy for the prevention of diabetic neuropathy.
10.2174/1871530319666191022114139
Schwann cell functions in peripheral nerve development and repair.
Neurobiology of disease
The glial cell of the peripheral nervous system (PNS), the Schwann cell (SC), counts among the most multifaceted cells of the body. During development, SCs secure neuronal survival and participate in axonal path finding. Simultaneously, they orchestrate the architectural set up of the developing nerves, including the blood vessels and the endo-, peri- and epineurial layers. Perinatally, in rodents, SCs radially sort and subsequently myelinate individual axons larger than 1 μm in diameter, while small calibre axons become organised in non-myelinating Remak bundles. SCs have a vital role in maintaining axonal health throughout life and several specialized SC types perform essential functions at specific locations, such as terminal SC at the neuromuscular junction (NMJ) or SC within cutaneous sensory end organs. In addition, neural crest derived satellite glia maintain a tight communication with the soma of sensory, sympathetic, and parasympathetic neurons and neural crest derivatives are furthermore an indispensable part of the enteric nervous system. The remarkable plasticity of SCs becomes evident in the context of a nerve injury, where SC transdifferentiate into intriguing repair cells, which orchestrate a regenerative response that promotes nerve repair. Indeed, the multiple adaptations of SCs are captivating, but remain often ill-resolved on the molecular level. Here, we summarize and discuss the knowns and unknowns of the vast array of functions that this single cell type can cover in peripheral nervous system development, maintenance, and repair.
10.1016/j.nbd.2022.105952
Role of macrophages in Wallerian degeneration and axonal regeneration after peripheral nerve injury.
Chen Peiwen,Piao Xianhua,Bonaldo Paolo
Acta neuropathologica
The peripheral nervous system (PNS) has remarkable regenerative abilities after injury. Successful PNS regeneration relies on both injured axons and non-neuronal cells, including Schwann cells and immune cells. Macrophages are the most notable immune cells that play key roles in PNS injury and repair. Upon peripheral nerve injury, a large number of macrophages are accumulated at the injury sites, where they not only contribute to Wallerian degeneration, but also are educated by the local microenvironment and polarized to an anti-inflammatory phenotype (M2), thus contributing to axonal regeneration. Significant progress has been made in understanding how macrophages are educated and polarized in the injured microenvironment as well as how they contribute to axonal regeneration. Following the discussion on the main properties of macrophages and their phenotypes, in this review, we will summarize the current knowledge regarding the mechanisms of macrophage infiltration after PNS injury. Moreover, we will discuss the recent findings elucidating how macrophages are polarized to M2 phenotype in the injured PNS microenvironment, as well as the role and underlying mechanisms of macrophages in peripheral nerve injury, Wallerian degeneration and regeneration. Furthermore, we will highlight the potential application by targeting macrophages in treating peripheral nerve injury and peripheral neuropathies.
10.1007/s00401-015-1482-4
Mechanisms of Schwann cell plasticity involved in peripheral nerve repair after injury.
Cellular and molecular life sciences : CMLS
The great plasticity of Schwann cells (SCs), the myelinating glia of the peripheral nervous system (PNS), is a critical feature in the context of peripheral nerve regeneration following traumatic injuries and peripheral neuropathies. After a nerve damage, SCs are rapidly activated by injury-induced signals and respond by entering the repair program. During the repair program, SCs undergo dynamic cell reprogramming and morphogenic changes aimed at promoting nerve regeneration and functional recovery. SCs convert into a repair phenotype, activate negative regulators of myelination and demyelinate the damaged nerve. Moreover, they express many genes typical of their immature state as well as numerous de-novo genes. These genes modulate and drive the regeneration process by promoting neuronal survival, damaged axon disintegration, myelin clearance, axonal regrowth and guidance to their former target, and by finally remyelinating the regenerated axon. Many signaling pathways, transcriptional regulators and epigenetic mechanisms regulate these events. In this review, we discuss the main steps of the repair program with a particular focus on the molecular mechanisms that regulate SC plasticity following peripheral nerve injury.
10.1007/s00018-020-03516-9
Pathophysiology of peripheral nerve injury: a brief review.
Burnett Mark G,Zager Eric L
Neurosurgical focus
Clinicians caring for patients with brachial plexus and other nerve injuries must possess a clear understanding of the peripheral nervous system's response to trauma. In this article, the authors briefly review peripheral nerve injury (PNI) types, discuss the common injury classification schemes, and describe the dynamic processes of degeneration and reinnervation that characterize the PNI response.
10.3171/foc.2004.16.5.2