Involvement of monocyte chemoattractant protein-1, macrophage inflammatory protein-1alpha and interleukin-1beta in Wallerian degeneration.
Perrin Florence E,Lacroix Steve,Avilés-Trigueros Marcelino,David Samuel
Brain : a journal of neurology
Wallerian degeneration in the CNS and PNS consists of degradation and phagocytosis of axons and their myelin sheath distal to the site of injury. This process of degeneration, which requires an effective macrophage response, occurs rapidly in peripheral nerves but is slow in the CNS. Rapid Wallerian degeneration in peripheral nerves may contribute to subsequent axonal regeneration. We show that there is a marked increase in mRNA expression of three pro-inflammatory molecules, the chemokines monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1alpha (MIP-1alpha), and the cytokine interleukin-1beta (IL-1beta), in the mouse sciatic nerve but not in the spinal cord undergoing Wallerian degeneration. Neutralizing MCP-1, MIP-1alpha and IL-1beta in the lesioned sciatic nerve with function-blocking antibodies suppressed macrophage responses and myelin clearance. Injecting recombinant MCP-1, MIP-1alpha or IL-1beta into the normal, uninjured spinal cord triggered the expression of a number of chemokines and cytokines. Furthermore, injecting recombinant MCP-1/MIP-1alpha or IL-1beta into the dorsal column of the spinal cord undergoing Wallerian degeneration triggered rapid macrophage/microglial activation and myelin clearance. These findings provide direct evidence that MCP-1, MIP-1alpha and IL-1beta are important regulators of macrophage responses that lead to rapid myelin breakdown and clearance in Wallerian degeneration.
10.1093/brain/awh407
Protective role of anakinra against transthyretin-mediated axonal loss and cell death in a mouse model of familial amyloidotic polyneuropathy.
Gonçalves Nádia Pereira,Teixeira-Coelho Maria,Saraiva Maria João
Journal of neuropathology and experimental neurology
Familial amyloidotic polyneuropathy (FAP) is characterized by a length-dependent axonal loss in the peripheral nervous system that results from deposition of extracellular prefibrillar transthyretin (TTR) and amyloid fibrils. We have previously shown that an inflammatory stimulus in the peripheral nerve in a mouse model of FAP triggers local TTR expression and deposition, leading to poor regeneration. We also demonstrated that blocking interleukin-1 (IL-1) signaling by the IL-1 receptor antagonist anakinra is beneficial in preventing nerve TTR deposition and associated toxicity. Here, we investigated whether IL-1 signaling influences TTR biology after an injury stimulus in a V30M FAP mouse model. Animals were treated with anakinra 48 hours before sciatic nerve ligation; the nerves were analyzed 7 days postlesion. Anakinra decreased TTR expression by Schwann cells and TTR extracellular deposition after nerve injury, which resulted in improved regeneration. Moreover, treated mice had less apoptotic cell death. In wild-type mice, inflammation is important for regeneration but, in the FAP model mice, an altered threshold of the inflammatory response differentially regulates TTR. Taken together, our results show that anakinra administration before injury can modulate TTR-induced peripheral nervous system pathology, thereby corroborating the protective interference of this drug in a FAP preclinical model.
10.1097/NEN.0000000000000164
Dynamic control of proinflammatory cytokines Il-1β and Tnf-α by macrophages in zebrafish spinal cord regeneration.
Tsarouchas Themistoklis M,Wehner Daniel,Cavone Leonardo,Munir Tahimina,Keatinge Marcus,Lambertus Marvin,Underhill Anna,Barrett Thomas,Kassapis Elias,Ogryzko Nikolay,Feng Yi,van Ham Tjakko J,Becker Thomas,Becker Catherina G
Nature communications
Spinal cord injury leads to a massive response of innate immune cells in non-regenerating mammals, but also in successfully regenerating zebrafish. However, the role of the immune response in successful regeneration is poorly defined. Here we show that inhibiting inflammation reduces and promoting it accelerates axonal regeneration in spinal-lesioned zebrafish larvae. Mutant analyses show that peripheral macrophages, but not neutrophils or microglia, are necessary for repair. Macrophage-less irf8 mutants show prolonged inflammation with elevated levels of Tnf-α and Il-1β. Inhibiting Tnf-α does not rescue axonal growth in irf8 mutants, but impairs it in wildtype animals, indicating a pro-regenerative role of Tnf-α. In contrast, decreasing Il-1β levels or number of Il-1β neutrophils rescue functional regeneration in irf8 mutants. However, during early regeneration, interference with Il-1β function impairs regeneration in irf8 and wildtype animals. Hence, inflammation is dynamically controlled by macrophages to promote functional spinal cord regeneration in zebrafish.
10.1038/s41467-018-07036-w
Investigation of the effect of telmisartan on experimentally induced peripheral nerve injury in rats.
Yuksel Tugba Nurcan,Halici Zekai,Demir Recep,Cakir Murteza,Calikoglu Cagatay,Ozdemir Gokhan,Unal Deniz
The International journal of neuroscience
AIM:The aim of this study was to investigate the effects of telmisartan on nerve healing in a rat peripheral nerve injury model. MATERIAL AND METHOD:Thirty adult male Wistar albino rats were divided into five groups: healthy, axonotmesis, anastomosis, axonotmesis+10 mg/kg telmisartan and anastomosis+10 mg/kg telmisartan. Walking track analyses were performed 4 weeks after the surgery. The right sciatic nerves of all the animals were examined histopathologically, stereologically and molecularly. RESULTS:Many badly damaged axons were detected in the axonotmesis group, in addition to enlarged spaces between the axons. In the anastomosis group, both ir- regular and degenerated axons at different severities were observed. The sections of the telmisartan group after the axonotmesis were similar to those of the healthy group. The sections of the telmisartan group after the anastomosis were similar to those of the healthy group and the telmisartan group after the axonotmesis. Interleukin-1 beta (IL-1β) gene expression increased in both the axonotmesis and the anastomosis groups when compared with the healthy group. Telmisartan had a significant down-regulatory effect on IL-1β expression. Caspase-3 mRNA expression was significantly increased in the anastomosis group, and the administration of telmisartan in this group significantly decreased this rise in caspase-3 mRNA expression. As a functional outcome, telmisartan also increased the walking distance of the rats after axonotmesis and anastomosis. CONCLUSION:The histopathological, stereological, functional and molecular data suggest that telmisartan improves nerve regeneration in peripheral nerve injuries by inhibiting inflammatory cytokine IL-1β and apoptotic caspase-3.
10.3109/00207454.2014.948115
Electrical Sympathetic Neuromodulation Protects Bone Marrow Niche and Drives Hematopoietic Regeneration during Chemotherapy.
Small methods
The sympathetic nervous system (SNS) of the bone marrow regulates the regeneration and mobilization of hematopoietic stem cells. Chemotherapy can damage bone marrow SNS, which impairs hematopoietic regeneration and aggravates hematologic toxicities. This leads to long-term bone marrow niche damage and increases mortality in patients undergoing chemotherapy. Electrical neuromodulation has been used to improve functional recovery after peripheral nerve injury. This study demonstrates that electrical sympathetic neuromodulation (ESN) of bone marrow can protect the bone marrow niche from chemotherapy-induced injury. Using carboplatin-treated rats, the SNS via the sciatic nerve innervating the femoral marrow with the effective protocol for bone marrow sympathetic activation is electrically stimulated. ESN can mediate several hematopoietic stem cells maintenance factors and promote hematopoietic regeneration after chemotherapy. It also activates adrenergic signals and reduces the release of pro-inflammatory cytokines, particularly interleukin-1 β, which contribute to chemotherapy-related nerve injury. Consequently, the severity of chemotherapy-related leukopenia, thrombocytopenia, and mortality can be reduced by ESN. As a result, in contrast to current drug-based treatment, such as granulocyte colony-stimulating factor, ESN can be a disruptive adjuvant treatment by protecting and modulating bone marrow function to reduce hematologic toxicity during chemotherapy.
10.1002/smtd.202201300
A disintegrin and metalloprotease with thrombospondin type1 motifs (ADAMTS-1) and IL-1 receptor type 1 mRNAs are simultaneously induced in nerve injured motor neurons.
Sasaki M,Seo-Kiryu S,Kato R,Kita S,Kiyama H
Brain research. Molecular brain research
Following rat hypoglossal nerve injury, expression of mRNAs for a disintegrin and metalloprotease with thrombospondin type1 motifs (ADAMTS-1) and IL-1 receptor type 1 (IL-1RT1) are induced in the injured motor neurons. Although N1E-115 (N1E) cells, which were treated with IL-1 alpha, showed no alteration of ADAMTS-1 mRNA expression, a substantial increase of ADAMTS-1 mRNA expression was observed in the N1E cells expressing IL-1RT1. These findings suggest that nerve injury promotes IL-1RT1 expression in the injured neurons and thereby ADAMTS-1 transcription was induced in response to IL-1 released from glial cells.
A conditioning lesion promotes in vivo nerve regeneration in the contralateral sciatic nerve of rats.
Ryoke K,Ochi M,Iwata A,Uchio Y,Yamamoto S,Yamaguchi H
Biochemical and biophysical research communications
A conditioning lesion in the sciatic nerve increases in vivo axonal regeneration in the nerve after a second transection. We studied whether this increased regeneration also occurs in the contralateral nerve. The left sciatic nerve was transected and sutured in Wistar rats; the nerve was exposed but not transected in controls. After 5 days, the right sciatic nerves of all rats were transected and sutured. Neuronal regeneration was measured at 0, 1, 3, 5, and 7 days with the pinch test and histological staining. IL-1beta and TGF-beta1 expression was also measured. The initial delay in the experimental group was significantly shorter, but the regeneration rates were the same. The expression of IL-1beta and TGF-beta1 in the right dorsal root ganglia was significantly higher in the experimental group. Nerve injury enhances cytokine expression in the contralateral dorsal root ganglion and promotes contralateral nerve regeneration in vivo by shortening the initial delay.
10.1006/bbrc.1999.2017
Characterization of Novel SARM1 Inhibitors for the Treatment of Chemotherapy-Induced Peripheral Neuropathy.
Biomedicines
BACKGROUND:Sterile α and Toll/IL-1 receptor motif-containing 1 (SARM1) is a central regulator of programmed axon death and a crucial nicotinamide adenine dinucleotide (NAD+) hydrolase (NADase) in mammalian tissues, hydrolyzing NAD+ and playing an important role in cellular NAD+ recycling. Abnormal SARM1 expression is linked to axon degeneration, which causes disability and disease progression in many neurodegenerative disorders of the peripheral and central nervous systems. METHODS:In this study, we use PC6 assay of hydrolase activity, DRG axon regeneration and CIPN model to screen for potent SARM1 Inhibitors. RESULTS:Two novel SARM1 inhibitors (compound 174 and 331P1) are charcterized for its high potency for SARM1 NADase. In a chemotherapy-induced peripheral neuropathy (CIPN) myopathy model, compound 331P1 treatment prevented the decline in neurofilament light chain (NfL) levels caused by axonal injury in a dose-dependent manner, associated with elevated intraepidermal nerve fiber (IENF) intensity in mouse foot paw tissue, suggesting its functionality in reversing axon degeneration. CONCLUSIONS:The newly designed SARM1 inhibitor 331P1 is a promising candidate due to its excellent in vivo efficacy, favorable CYP inhibition properties, and attractive safety profiles. The 331P1 compound possesses the potential to be developed as a novel neuroprotective therapy that can prevent or halt the neurodegenerative process in CIPN.
10.3390/biomedicines12092123
Interleukin-1 beta promotes functional recovery of crushed peripheral nerve.
Korompilias A V,Chen L E,Seaber A V,Urbaniak J R
Journal of orthopaedic research : official publication of the Orthopaedic Research Society
This study was conducted to elucidate the role of the cytokine interleukin-1 beta on peripheral nerve recovery following crush injuries of two different magnitudes. Eighty-eight female rats were divided into four groups. A 5-mm segment of the right sciatic nerve was subjected to a 100-g crush load for 2 hours in the rats in Groups A1 and B1 or to a 15,000-g crush load for 10 minutes in the rats in Groups A2 and B2. The rats in Groups A1 and A2 received 10 microg/100 g body weight human recombinant interleukin-1 beta intraperitoneally 48, 24, and 1 hours before the nerve injury. The rats in Groups B1 and B2 were treated with an equal volume of normal saline solution with identical schedule guidelines. Walking-track tests (sciatic functional index) performed at intervals until 56 days after the crush and measurements of the contractile force of the extensor digitorum longus muscle made until 28 days were used to evaluate functional recovery of the nerve. During the second week after injury, the rats treated with interleukin-1 beta (A1) had an earlier recovery on the walking track than did those treated with saline solution (B1); this difference reached significance (p < 0.05) at day 11. Although Group A2 demonstrated a trend toward earlier recovery compared with Group B2, there was no significant difference between the two groups. After low or high-load crush injury, tetanic contractile forces were greater in the rats treated with human recombinant interleukin-1 beta than in those treated with saline solution. The results suggest that treatment with human recombinant interleukin-1 beta before crush injury can promote function in the peripheral nerve after the injury. However, the mechanisms that underlie the observed beneficial effects are not completely understood and only speculations can be made.
10.1002/jor.1100170514
Interleukin-1β influences functional regeneration following nerve injury in mice through nuclear factor-κB signaling pathway.
Wu Ruoyu,Chen Bi,Jia Xiang,Qiu Yu,Liu Mengyu,Huang Chengsheng,Feng Jie,Wu Qingkai
Immunology
This study focuses on investigating the role of interleukin-1β (IL-1β) in functional regeneration following nerve injury in mice. A microarray-based mRNA profiling study was used to analyze the expression level of IL-1β in peripheral nerve regeneration. Quantitative real-time polymerase chain reaction and Western blot were applied to assess the IL-1β expressions of C57BL/6J-crush and C57BL/6J-crush+IL-1β mice at different post-injury time-points after the standard sciatic nerve crush injury. The outcomes of nerve regeneration were evaluated by behavioral tests. IL-1β was found to be up-regulated in peripheral nerve regeneration and significantly raised on the 3rd day and returned to normal levels on the 14th day after nerve injury. Compared with C57BL/6J-crush+IL-1β mice, the nerve regeneration of C57BL/6J-crush mice was worse after nerve crush injury. IL-1β increased mechanical sensitivity and stimulated amplitude. IL-1β could benefit the recovery of sciatic nerve crush injury by facilitating nerve regeneration.
10.1111/imm.13022
The effect of charge-balanced transcutaneous electrical nerve stimulation on rodent facial nerve regeneration.
Scientific reports
This study aimed to investigate the effect of charge-balanced transcutaneous electrical nerve stimulation (cb-TENS) in accelerating recovery of the facial function and nerve regeneration after facial nerve (FN) section in a rat model. The main trunk of the left FN was divided and immediately sutured just distal to the stylomastoid foramen in 66 Sprague-Dawley rats. The control group had no electrical stimulus. The other two groups received cb-TENS at 20 Hz (20 Hz group) or 40 Hz (40 Hz group). Cb-TENS was administered daily for seven days and then twice a week for three weeks thereafter. To assess the recovery of facial function, whisker movement was monitored for four weeks. Histopathological evaluation of nerve regeneration was performed using transmission electron microscopy (TEM) and confocal microscopy with immunofluorescence (IF) staining. In addition, the levels of various molecular biological markers that affect nerve regeneration were analyzed. Whisker movement in the cb-TENS groups showed faster and better recovery than the control group. The 40 Hz group showed significantly better movement at the first week after injury (p < 0.0125). In histopathological analyses using TEM, nerve axons and Schwann cells, which were destroyed immediately after the injury, recovered in all groups over time. However, the regeneration of the myelin sheath was remarkably rapid and thicker in the 20 Hz and 40 Hz groups than in the control group. Image analysis using IF staining showed that the expression levels of S100B and NF200 increased over time in all groups. Specifically, the expression of NF200 in the 20 Hz and 40 Hz groups increased markedly compared to the control group. The real-time polymerase chain reaction was performed on ten representative neurotrophic factors, and the levels of IL-1β and IL-6 were significantly higher in the 20 and 40 Hz groups than in the control group (p < 0.015). Cb-TENS facilitated and accelerated FN recovery in the rat model, as it significantly reduced the recovery time for the whisker movement. The histopathological study and analysis of neurotrophic factors supported the role of cb-TENS in the enhanced regeneration of the FN.
10.1038/s41598-022-05542-y
Limonene, a food additive, and its active metabolite perillyl alcohol improve regeneration and attenuate neuropathic pain after peripheral nerve injury: Evidence for IL-1β, TNF-α, GAP, NGF and ERK involvement.
Araújo-Filho Heitor G,Pereira Erik W M,Heimfarth Luana,Souza Monteiro Brenda,Santos Passos Fabiolla Rocha,Siqueira-Lima Pollyana,Gandhi Sathiyabama R,Viana Dos Santos Márcio Roberto,Guedes da Silva Almeida Jackson Roberto,Picot Laurent,Grougnet Raphaël,Almeida Ray S,Douglas Melo Coutinho Henrique,Quintans-Júnior Lucindo J,Martins Natália,Quintans Jullyana S S
International immunopharmacology
BACKGROUND:Limonene (LIM) and its main metabolite perillyl alcohol (POH) are ingredients found in food with promising chemical entities due to their pharmacological profile. In this study, we hypothesized that LIM and POH are two molecules capable of accelerating the regenerative process and alleviating neuropathic pain. METHODS:Animals were treated daily (LIM, POH and saline) for 28 days and during this period evaluated for mechanical hyperalgesia, astrocyte participation by immunofluorescence for GFAP, and ELISA was used to quantify IL-1β and TNF-α in the spinal cord. Western blot analysis of the following proteins was also performed: GFAP, GAP-43, NGF and ERK. For motor deficit analysis, tests were performed to assess hind paw muscle strength and footprints through gait (SFI). RESULTS:Both POH and LIM accelerated the regenerative process and improved motor deficits comparing to positive control; however, POH was more effective, particularly between the 2nd and 3rd week after the nerve injury, increasing GAP-43, NGF and the phosphorylated ERK immunocontent. Moreover, POH and LIM were able to reduce hyperalgesia and astrocytosis. CONCLUSIONS:Both substances, LIM and POH, improved the regeneration process and sensory and motor function recovery in the PNI model in mice by mitigating the inflammatory reactions and up-regulating the neurotrophic process.
10.1016/j.intimp.2020.106766
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
Functional recovery after peripheral nerve injury is dependent on the pro-inflammatory cytokines IL-1β and TNF: implications for neuropathic pain.
Nadeau Sylvain,Filali Mohammed,Zhang Ji,Kerr Bradley J,Rivest Serge,Soulet Denis,Iwakura Yoichiro,de Rivero Vaccari Juan Pablo,Keane Robert W,Lacroix Steve
The Journal of neuroscience : the official journal of the Society for Neuroscience
IL-1β and TNF are potential targets in the management of neuropathic pain after injury. However, the importance of the IL-1 and TNF systems for peripheral nerve regeneration and the mechanisms by which these cytokines mediate effects are to be fully elucidated. Here, we demonstrate that mRNA and protein levels of IL-1β and TNF are rapidly upregulated in the injured mouse sciatic nerve. Mice lacking both IL-1β and TNF, or both IL-1 type 1 receptor (IL-1R1) and TNF type 1 receptor (TNFR1), showed reduced nociceptive sensitivity (mechanical allodynia) compared with wild-type littermates after injury. Microinjecting recombinant IL-1β or TNF at the site of sciatic nerve injury in IL-1β- and TNF-knock-out mice restored mechanical pain thresholds back to levels observed in injured wild-type mice. Importantly, recovery of sciatic nerve function was impaired in IL-1β-, TNF-, and IL-1β/TNF-knock-out mice. Notably, the infiltration of neutrophils was almost completely prevented in the sciatic nerve distal stump of mice lacking both IL-1R1 and TNFR1. Systemic treatment of mice with an anti-Ly6G antibody to deplete neutrophils, cells that play an essential role in the genesis of neuropathic pain, did not affect recovery of neurological function and peripheral axon regeneration. Together, these results suggest that targeting specific IL-1β/TNF-dependent responses, such as neutrophil infiltration, is a better therapeutic strategy for treatment of neuropathic pain after peripheral nerve injury than complete blockage of cytokine production.
10.1523/JNEUROSCI.2840-11.2011
Increased Calcitonin Gene-Related Peptide and Macrophages Are Involved in Astragalus membranaceus-Mediated Peripheral Nerve Regeneration in Rats.
Chen Chung-Chia,Chang Ling-Chuan,Yao Chun-Hsu,Hsu Yuan-Man,Lin Jia-Horng,Yang Tse-Yen,Chen Yung-Hsiang,Chen Yueh-Sheng
The American journal of Chinese medicine
Astragalus membranaceus (AM) is one of 50 fundamental herbs in traditional Chinese medicine. Previous studies have shown that AM extract can be a potential nerve growth-promoting factor, being beneficial for the growth of peripheral nerve axons. We further investigated the effects of AM extract on regeneration in a rat sciatic nerve transection model. Rats were divided into three groups ([Formula: see text]): normal saline (intraperitoneal) as the control, and 1.5[Formula: see text]g/kg or 3.0[Formula: see text]g/kg of AM extract (every other day for four weeks), respectively. We evaluated neuronal electrophysiology, neuronal connectivity, macrophage infiltration, expression levels and location of calcitonin gene-related peptide (CGRP), and expression levels of both nerve growth factors (NGFs) and immunoregulatory factors. In the high-dose AM group, neuronal electrophysiological function (measured by nerve conductive velocity and its latency) was significantly improved ([Formula: see text]). Expression levels of CGRP and macrophage density were also drastically enhanced ([Formula: see text]). Expression levels of fibroblast growth factor (FGF), NGF, platelet-derived growth factor (PDGF), transforming growth factor-[Formula: see text], interleukin-1 (IL-1), and interferon (IFN)-[Formula: see text] were reduced in the high-dose AM group ([Formula: see text]), while FGF, NGF, PDGF, IL-1, and IFN-[Formula: see text] were increased in the low-dose AM group ([Formula: see text]). These results suggest that AM can modulate local inflammatory conditions, enhance nerve regeneration, and potentially increase recovery of a severe peripheral nerve injury.
10.1142/S0192415X18500040
Peripheral nerve regeneration is impeded by interleukin-1 receptor antagonist released from a polymeric guidance channel.
Guénard V,Dinarello C A,Weston P J,Aebischer P
Journal of neuroscience research
Interleukin-1 receptor antagonist (IL-1ra), a true antagonist of the interleukin-1 (IL-1) receptors, is released by activated macrophages and binds specifically to the IL-1 receptors without triggering IL-1 effects. Following peripheral nerve axotomy, activated macrophages release IL-1, which induces the expression of nerve growth factor (NGF) mRNA in Schwann cells. IL-1ra may therefore impede peripheral nerve regeneration by blocking the NGF-mediated effect of IL-1. Peripheral nerve regeneration occurring through polymeric guidance channels releasing IL-1ra was investigated in a 4-mm gap transected mouse sciatic nerve model. Cohorts of five animals were implanted with tubes releasing either bovine serum albumin (BSA), BSA with IL-1ra, or BSA with deactivated IL-1ra (dIL-1ra) for 4 weeks. In vitro release kinetics indicated that after an initial burst, IL-1ra release was linear for the next 3 1/2 weeks. Following implantation of a polymeric guidance channel, a regenerated cable bridged the nerve gap in all animals. The cables were similar in size and were composed of nerve microfascicles containing both unmyelinated and myelinated axons in association with their Schwann cells. Tissue regenerated in tubes releasing BSA-IL-1ra contained, however, significantly fewer myelinated and unmyelinated axons and blood vessels than did tubes releasing BSA alone or BSA-dIL-1ra. We conclude that a naturally occurring antagonist of IL-1 receptors impedes peripheral nerve regeneration, suggesting that macrophages play an essential role in controlling peripheral nerve regeneration through the release of stimulatory and/or inhibitory molecules.
10.1002/jnr.490290315
Interleukin (IL)-1 Receptor Signaling Is Required for Complete Taste Bud Regeneration and the Recovery of Neural Taste Responses following Axotomy.
The Journal of neuroscience : the official journal of the Society for Neuroscience
Experimental or traumatic nerve injury causes the degeneration of associated taste buds. Unlike most sensory systems, the sectioned nerve and associated taste buds can then regenerate, restoring neural responses to tastants. It was previously unknown whether injury-induced immune factors mediate this process. The proinflammatory cytokines, interleukin (IL)-1α and IL-1β, and their requisite receptor are strongly expressed by anterior taste buds innervated by the chorda tympani nerve. We tested taste bud regeneration and functional recovery in mice lacking the IL-1 receptor. After axotomy, the chorda tympani nerve regenerated but was initially unresponsive to tastants in both WT and mice. In the absence of signaling, however, neural taste responses remained minimal even >8 weeks after injury in both male and female mice, whereas normal taste function recovered by 3 weeks in WT mice. Failed recovery was because of a 57.8% decrease in regenerated taste buds in KO compared with WT axotomized mice. gene expression was chronically dysregulated, and the subset of regenerated taste buds were reinnervated more slowly and never reached full volume as progenitor cell proliferation lagged in KO mice. signaling is thus required for complete taste bud regeneration and the recovery of normal taste transmission, likely by impairing taste progenitor cell proliferation. This is the first identification of a cytokine response that promotes taste recovery. The remarkable plasticity of the taste system makes it ideal for identifying injury-induced mechanisms mediating successful regeneration and recovery. Taste plays a critical role in nutrition and quality of life. The adult taste system is highly plastic and able to regenerate following the disappearance of most taste buds after experimental nerve injury. Several growth factors needed for taste bud regeneration have been identified, but we demonstrate the first cytokine pathway required for the recovery of taste function. In the absence of IL-1 cytokine signaling, taste bud regeneration is incomplete, preventing the transmission of taste activity to the brain. These results open a new direction in revealing injury-specific mechanisms that could be harnessed to promote the recovery of taste perception after trauma or disease.
10.1523/JNEUROSCI.1355-22.2023
IL-1 beta enhances neurite regeneration from transected-nerve terminals of adult rat DRG.
Horie H,Sakai I,Akahori Y,Kadoya T
Neuroreport
We clarified the roles of IL-1 beta in peripheral neural regeneration after axotomy in a three-dimensional collagen gel culture system ranging from a single neurone to a dorsal root ganglion (DRG) explant with its associated nerve bundles. Application of 30 U/ml IL-1 beta to the culture systems clearly enhanced neural regeneration. This regeneration was evident in transected nerve terminals of DRG explants with or without associated nerve bundles, but not in dissociated single neurones. Neural survival was not affected by IL-1 beta in any of these culture systems. These results suggest that IL-1 beta stimulates surrounding non-neuronal cells to secrete neurotrophic factors, thus enhancing neurite regeneration from transected nerve terminals in cultured adult DRG explants.
10.1097/00001756-199705260-00032
Improved peripheral nerve regeneration in streptozotocin-induced diabetic rats by oral lumbrokinase.
Lee Han-Chung,Hsu Yuan-Man,Tsai Chin-Chuan,Ke Cherng-Jyh,Yao Chun-Hsu,Chen Yueh-Sheng
The American journal of Chinese medicine
We assessed the therapeutic effects of lumbrokinase, a group of enzymes extracted from the earthworm, on peripheral-nerve regeneration using well-defined sciatic nerve lesion paradigms in diabetic rats induced by the injection of streptozotocin (STZ). We found that lumbrokinase therapy could improve the rats' circulatory blood flow and promote the regeneration of axons in a silicone rubber conduit after nerve transection. Lumbrokinase treatment could also improve the neuromuscular functions with better nerve conductive performances. Immunohistochemical staining showed that lumbrokinase could dramatically promote calcitonin gene-related peptide (CGRP) expression in the lamina I-II regions in the dorsal horn ipsilateral to the injury and cause a marked increase in the number of macrophages recruited within the distal nerve stumps. In addition, the lumbrokinase could stimulate the secretion of interleukin-1 (IL-1), nerve growth factor (NGF), platelet-derived growth factor (PDGF), and transforming growth factor-β (TGF-β) in dissected diabetic sciatic nerve segments. In conclusion, the administration of lumbrokinase after nerve repair surgery in diabetic rats was found to have remarkable effects on promoting peripheral nerve regeneration and functional recovery.
10.1142/S0192415X15500147