Dendritic cell subsets in T cell programming: location dictates function.
Nature reviews. Immunology
Dendritic cells (DCs) can be viewed as translators between innate and adaptive immunity. They integrate signals derived from tissue infection or damage and present processed antigen from these sites to naive T cells in secondary lymphoid organs while also providing multiple soluble and surface-bound signals that help to guide T cell differentiation. DC-mediated tailoring of the appropriate T cell programme ensures a proper cascade of immune responses that adequately targets the insult. Recent advances in our understanding of the different types of DC subsets along with the cellular organization and orchestration of DC and lymphocyte positioning in secondary lymphoid organs over time has led to a clearer understanding of how the nature of the T cell response is shaped. This Review discusses how geographical organization and ordered sequences of cellular interactions in lymph nodes and the spleen regulate immunity.
10.1038/s41577-018-0088-1
NLRP inflammasomes in health and disease.
Molecular biomedicine
NLRP inflammasomes are a group of cytosolic multiprotein oligomer pattern recognition receptors (PRRs) involved in the recognition of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) produced by infected cells. They regulate innate immunity by triggering a protective inflammatory response. However, despite their protective role, aberrant NLPR inflammasome activation and gain-of-function mutations in NLRP sensor proteins are involved in occurrence and enhancement of non-communicating autoimmune, auto-inflammatory, and neurodegenerative diseases. In the last few years, significant advances have been achieved in the understanding of the NLRP inflammasome physiological functions and their molecular mechanisms of activation, as well as therapeutics that target NLRP inflammasome activity in inflammatory diseases. Here, we provide the latest research progress on NLRP inflammasomes, including NLRP1, CARD8, NLRP3, NLRP6, NLRP7, NLRP2, NLRP9, NLRP10, and NLRP12 regarding their structural and assembling features, signaling transduction and molecular activation mechanisms. Importantly, we highlight the mechanisms associated with NLRP inflammasome dysregulation involved in numerous human auto-inflammatory, autoimmune, and neurodegenerative diseases. Overall, we summarize the latest discoveries in NLRP biology, their forming inflammasomes, and their role in health and diseases, and provide therapeutic strategies and perspectives for future studies about NLRP inflammasomes.
10.1186/s43556-024-00179-x
The role of serotonin and its receptors in activation of immune responses and inflammation.
Shajib M S,Khan W I
Acta physiologica (Oxford, England)
Serotonin or 5-hydroxytryptamine (5-HT) is a neurotransmitter and hormone that contributes to the regulation of various physiological functions by its actions in the central nervous system (CNS) and in the respective organ systems. Peripheral 5-HT is predominantly produced by enterochromaffin (EC) cells of the gastrointestinal (GI) tract. These gut-resident cells produce much more 5-HT than all neuronal and other sources combined, establishing EC cells as the main source of this biogenic amine in the human body. Peripheral 5-HT is also a potent immune modulator and affects various immune cells through its receptors and via the recently identified process of serotonylation. Alterations in 5-HT signalling have been described in inflammatory conditions of the gut, such as inflammatory bowel disease. The association between 5-HT and inflammation, however, is not limited to the gut, as changes in 5-HT levels have also been reported in patients with allergic airway inflammation and rheumatoid arthritis. Based on searches for terms such as '5-HT', 'EC cell', 'immune cells' and 'inflammation' in pubmed.gov as well as by utilizing pertinent reviews, the current review aims to provide an update on the role of 5-HT in biological functions with a particular focus on immune activation and inflammation.
10.1111/apha.12430
Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery.
Ito Minako,Komai Kyoko,Mise-Omata Setsuko,Iizuka-Koga Mana,Noguchi Yoshiko,Kondo Taisuke,Sakai Ryota,Matsuo Kazuhiko,Nakayama Takashi,Yoshie Osamu,Nakatsukasa Hiroko,Chikuma Shunsuke,Shichita Takashi,Yoshimura Akihiko
Nature
In addition to maintaining immune tolerance, FOXP3 regulatory T (T) cells perform specialized functions in tissue homeostasis and remodelling. However, the characteristics and functions of brain T cells are not well understood because there is a low number of T cells in the brain under normal conditions. Here we show that there is massive accumulation of T cells in the mouse brain after ischaemic stroke, and this potentiates neurological recovery during the chronic phase of ischaemic brain injury. Although brain T cells are similar to T cells in other tissues such as visceral adipose tissue and muscle, they are apparently distinct and express unique genes related to the nervous system including Htr7, which encodes the serotonin receptor 5-HT. The amplification of brain T cells is dependent on interleukin (IL)-2, IL-33, serotonin and T cell receptor recognition, and infiltration into the brain is driven by the chemokines CCL1 and CCL20. Brain T cells suppress neurotoxic astrogliosis by producing amphiregulin, a low-affinity epidermal growth factor receptor (EGFR) ligand. Stroke is a leading cause of neurological disability, and there are currently few effective recovery methods other than rehabilitation during the chronic phase. Our findings suggest that T cells and their products may provide therapeutic opportunities for neuronal protection against stroke and neuroinflammatory diseases.
10.1038/s41586-018-0824-5
Serotonin transporter-deficient mice display enhanced adipose tissue inflammation after chronic high-fat diet feeding.
Frontiers in immunology
Introduction:Serotonin is involved in leukocyte recruitment during inflammation. Deficiency of the serotonin transporter (SERT) is associated with metabolic changes in humans and mice. A possible link and interaction between the inflammatory effects of serotonin and metabolic derangements in SERT-deficient mice has not been investigated so far. Methods:SERT-deficient ( ) and wild type (WT) mice were fed a high-fat diet, starting at 8 weeks of age. Metabolic phenotyping (metabolic caging, glucose and insulin tolerance testing, body and organ weight measurements, qPCR, histology) and assessment of adipose tissue inflammation (flow cytometry, histology, qPCR) were carried out at the end of the 19-week high-fat diet feeding period. In parallel, and WT mice received a control diet and were analyzed either at the time point equivalent to high-fat diet feeding or as early as 8-11 weeks of age for baseline characterization. Results:After 19 weeks of high-fat diet, and WT mice displayed similar whole-body and fat pad weights despite increased relative weight gain due to lower starting body weight in . In obese animals insulin resistance and liver steatosis were enhanced as compared to WT animals. Leukocyte accumulation and mRNA expression of cytokine signaling mediators were increased in epididymal adipose tissue of obese mice. These effects were associated with higher adipose tissue mRNA expression of the chemokine monocyte chemoattractant protein 1 and presence of monocytosis in blood with an increased proportion of pro-inflammatory Ly6C+ monocytes. By contrast, mice fed a control diet did not display adipose tissue inflammation. Discussion:Our observations suggest that SERT deficiency in mice is associated with inflammatory processes that manifest as increased adipose tissue inflammation upon chronic high-fat diet feeding due to enhanced leukocyte recruitment.
10.3389/fimmu.2023.1184010
Serotonin activates dendritic cell function in the context of gut inflammation.
Li Nan,Ghia Jean-Eric,Wang Huaqing,McClemens Jessica,Cote Francine,Suehiro Youko,Mallet Jacques,Khan Waliul I
The American journal of pathology
Mucosal inflammation in the gut is characterized by infiltration of innate and adaptive immune cells and by an alteration in serotonin-producing enterochromaffin cells. We investigated the role of serotonin in the function of dendritic cells (DCs) and sequential T-cell activation in relation to generation of gut inflammation. DCs isolated from tryptophan hydroxylase-1-deficient (TPH1(-/-)) mice, which have reduced serotonin in the gut, and wild-type (TPH1(+/+)) mice with or without dextran sulfate sodium (DSS)-induced colitis were stimulated with lipopolysaccharide to assess interleukin-12 (IL-12) production. Isolated DCs from TPH1(+/+) and TPH1(-/-) mice were also cocultured with CD4(+) T cells of naive TPH1(+/+) mice to assess the role of serotonin in priming T cells. In addition, serotonin-pulsed DCs were transferred to TPH1(-/-) mice to assess the effect on DSS-induced colitis. Consistent with a reduced severity of colitis, DCs from DSS-induced TPH1(-/-) mice produced less IL-12 compared with the TPH1(+/+) mice. In vitro serotonin stimulation restored the cytokine production from TPH1(-/-) DCs and adoptive transfer of serotonin-pulsed DCs into TPH1(-/-) up-regulated colitis. Furthermore, CD4(+) T cells primed by TPH1(-/-) DCs produce reduced the levels of IL-17 and interferon-γ. This study provides novel information on serotonin-mediated immune signaling and promotion of interactions between innate and adaptive immune responses in the context of gut inflammation, which may ultimately lead to improved strategies to combat gut inflammatory disorders.
10.1016/j.ajpath.2010.10.028
Serotonin modulation of macrophage polarization: inflammation and beyond.
de Las Casas-Engel Mateo,Corbí Angel L
Advances in experimental medicine and biology
Macrophages display a ample plethora of effector functions whose acquisition is promoted by the surrounding cytokine and cellular environment. Depending on the stimulus, macrophages become specialized ("polarized") for either pathogen elimination, tissue repair and wound healing or immunosuppression. This "polarization" versatility allows macrophages to critically contribute to tissue homeostasis, as they promote initiation and resolution of inflammatory responses. As a consequence, deregulation of the tissue macrophage polarization balance is an etiological agent of chronic inflammation, autoimmune diseases, cancer and even obesity and insulin resistance. In the present review we describe current concepts on the molecular basis and the patho-physiological implications of macrophage polarization, and describe its modulation by serotonin (5-HT), a neurotransmitter that regulates inflammation and tissue repair via a large set of receptors (5-HTR1-7). 5-HT modulates the phenotypic and functional polarization of macrophages, and contributes to the maintenance of an anti-inflammatory state mainly via 5-HTR2B and 5-HTR7, whose activation has a great impact on macrophage gene expression profile. The identification of 5-HTR2B and 5-HTR7 as functionally-relevant polarization markers suggests their therapeutic value in inflammatory pathologies as well as their potential involvement in linking the immune and nervous systems.
10.1007/978-3-319-07320-0_9
Inflammation, serotonin and major depression.
Catena-Dell'Osso Mario,Rotella Francesco,Dell'Osso Adriana,Fagiolini Andrea,Marazziti Donatella
Current drug targets
The understanding of the neurobiological processes leading to major depressive disorder (MDD) is an active field of research in the scientific community. For years, the alteration of monoamine neurotransmission, in particular serotonin (5-HT), has been considered the most significant pathophysiological mechanism of the disorder. However, biological data supporting the postulated MDD-related monoamine alterations have been inconclusive, and the use of monoaminergic antidepressants has not yielded the expected results. In the last few years, it has been demonstrated that inflammatory pathways have a significant role in the pathophysiology of MDD. According to the cytokine hypothesis, the disorder would be due to a stress-related increased production of cytokines, including interleukins, tumor necrosis factor- α and interferon- α and γ . These, in turns, would cause the activation of the indoleamine 2,3 dioxygenase (IDO), with subsequent production of tryptophan (TRP) catabolites along the IDO pathway (TRYCATs) and decreased availability of TRP and 5-HT. Besides monoamines, other molecular mechanisms, as those within the inflammatory pathways, should be taken into account in the attempt to clarify the pathophysiology of MDD and to improve its treatment.
Beyond a neurotransmitter: The role of serotonin in inflammation and immunity.
Wu Hera,Denna Travis H,Storkersen Jordan N,Gerriets Valerie A
Pharmacological research
Serotonin (5-HT), a well-known neurotransmitter in the brain, also plays an important role in peripheral tissues, including the immune system. There is a growing body of evidence suggesting that many different types of immune cells express the machinery to generate, store, respond to and/or transport serotonin, including T cells, macrophages, mast cells, dendritic cells and platelets. In addition, there is emerging evidence of a possible connection between T cells, serotonin and mood disorders. How 5-HT interacts with the peripheral immune system and if this signaling is associated with behavioral phenotypes found in mood disorders like major depressive disorder (MDD) is not well understood. In this review, we summarize the existing literature on what is known about the link between 5-HT and the immune system and the effects of 5-HT signaling on different cells of the peripheral immune system, with a particular focus on T cells. In addition, we review the current evidence that peripheral immune system alterations and CNS function may be interrelated and the possible implications of these findings for drug discovery.
10.1016/j.phrs.2018.06.015