scholarly journals CX3CR1 But Not CCR2 Expression Is Required for the Development of Autoimmune Peripheral Neuropathy in Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Oladayo Oladiran ◽  
Xiang Qun Shi ◽  
Sylvie Fournier ◽  
Ji Zhang
Keyword(s):  
T Cells ◽  
Peripheral Neuropathy ◽  
Peripheral Nerves ◽  
Chemokine Receptors ◽  
Disease Onset ◽  
Autoimmune Response ◽  
Potential Contribution ◽  
Ccr2 Expression ◽  
Compensatory Proliferation ◽  
T Cell Survival

One hallmark of Guillain-Barre syndrome (GBS), a prototypic autoimmune peripheral neuropathy (APN) is infiltration of leukocytes (macrophages and T cells) into peripheral nerves, where chemokines and their receptors play major roles. In this study, we aimed to understand the potential contribution of chemokine receptors CCR2 and CX3CR1 in APN by using a well-established mouse model, B7.2 transgenic (L31) mice, which possesses a predisposed inflammatory background. We crossbred respectively CCR2KO and CX3CR1KO mice with L31 mice. The disease was initiated by partial ligation on one of the sciatic nerves. APN pathology and neurological function were evaluated on the other non-ligated sciatic nerve/limb. Our results revealed that L31/CX3CR1KO but not L31/CCR2KO mice were resistant to APN. CX3CR1 is needed for maintaining circulating monocyte and CD8+ T cell survival. While migration of a significant number of activated CD8+ T cells to peripheral nerves is essential in autoimmune response in nerve, recruitment of monocytes into PNS seems optional. Disease onset is independent of CCR2 mediated blood-derived macrophage recruitment, which can be replaced by compensatory proliferation of resident macrophages in peripheral nerve. CX3CR1 could also contribute to APN via its critical involvement in maintaining nerve macrophage phagocytic ability. We conclude that blockade of CX3CR1 signaling may represent an interesting anti-inflammatory strategy to improve therapeutic management for GBS patients.

scholarly journals Modification of the Disease Progression in Mice with Experimental Autoimmune Encephalomyelitis Using Anti-Mitotic Compounds

2021 ◽  
Author(s):  
◽  
Kevin Patrick Crume
Keyword(s):  
Nitric Oxide ◽  
T Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Disease Onset ◽  
Autoimmune Response ◽  
Peloruside A ◽  
Proliferating Cells ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

<p>Multiple sclerosis (MS) is a multi-faceted disease, and is believed to be caused by an autoimmune response to myelin antigens in the central nervous system. Experimental autoimmune encephalomyelitis (EAE), an animal model for MS. manifests itself in various forms that parallel many aspects of MS, including the appearance of symptoms, initiation events, and pathophysiology. The hallmark of any immune response is the antigen-specific proliferation of immune cells, and during the initiation events of EAE, proliferating CD4+ T cells are the primary mediators of disease. This thesis explores if targeting these proliferating cells with the anti-mitotic compounds paclitaxel and peloruside A can delay or prevent the unset of EAE, thus providing a novel therapeutic avenue for MS research. The anti-cancer compound, paclitaxel, is an anti-mitotic drug that prevents microtubule depolymerisation. Although paclitaxel has been used in the clinical setting to treat cancer for over a decade, it has been determined that paclitaxel stimulates murine toll-like receptor 4 (TLR4) complex, which is the major LPS receptor. A novel microtubule-stabilising compound, peloruside, is currently subject to intensive investigations due to its functional similarity to paclitaxel. The results from this project found that peloruside and paclitaxel inhibited the proliferation of mitogen-stimulated splenocytes with IC50 values of 83 nM and 30 nM, respectively, but did not affect the viability of non-proliferating cells In contrast to paclitaxel, peloruside did not cause the TLR4-mediated production of the inflammatory mediators. TNF-epsilon, IL-12, and nitric oxide, when cultured with IFN-epsilon stimulated murine macrophages. Interestingly, when LPS was included with either paclitaxel or peloruside A, both drugs decreased the production of TNF-e and nitric oxide from macrophages, suggesting that microtubule-stabilising compounds may have anti-inflammatory effects. To identify any immunomodifying effects of paclitaxel in vivo, paclitaxel was administered to mice that were immunised with the myelin protein MOG in complete Freund's adjuvant (CFA) to induce EAE. When Taxol was administered to mice for 5 consecutive days immediately following CFA/MOG immunisation, the onset of EAE was delayed by approximately I week. Moreover, the administration of peloruside following the same treatment regime also resulted in a similar delay of disease onset. Taxol treatments, however, lead to significant mortality in immunised, but not unimmunised mice. Interestingly, although Taxol is an anti-mitotic drug, the proliferation of antigen-specific T cells was not inhibited in vivo by the Taxol treatment. The findings revealed in this thesis present an opportunity to pursue a new avenue of research for the therapeutic treatment of MS sufferers, and possibly other inflammatory autoimmune disorders.</p>

scholarly journals Inhibition of TLR4 signaling protects mice from sensory and motor dysfunction in an animal model of autoimmune peripheral neuropathy

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Oladayo Oladiran ◽  
Xiang Qun Shi ◽  
Mu Yang ◽  
Sylvie Fournier ◽  
Ji Zhang
Keyword(s):  
Peripheral Neuropathy ◽  
T Cell Activation ◽  
Peripheral Nerves ◽  
Drug Target ◽  
Disease Onset ◽  
Intraperitoneal Administration ◽  
Motor Dysfunction ◽  
Tlr4 Signaling ◽  
Autoimmune Neuropathy ◽  
Molecular Patterns

Abstract Background While the etiology remains elusive, macrophages and T cells in peripheral nerves are considered as effector cells mediating autoimmune peripheral neuropathy (APN), such as Guillain-Barre syndrome. By recognizing both pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) signals, TLRs play a central role in the initiation of both innate and adaptive immune responses. In this study, we aimed to understand the involvement of TLR4 in the pathogenesis of APN and explore the potential of TLR4 as a drug target for therapeutic use. Methods APN was induced by a partial ligation on one of the sciatic nerves in B7.2 (L31) transgenic mice which possess a predisposed inflammatory background. APN pathology and neurological function were evaluated on the other non-injured sciatic nerve. Results TLR4 and its endogenous ligand HMGB1 were highly expressed in L31 mice, in circulating immune cells and in peripheral nerves. Enhanced TLR4 signaling was blocked with TAK 242, a selective TLR4 inhibitor, before and after disease onset. Intraperitoneal administration of TAK 242 not only inhibited monocyte, macrophage and CD8+ T cell activation, but also reduced the release of pro-inflammatory cytokines. TAK 242 protected mice from severe myelin and axonal loss, resulting in a remarkable improvement in mouse motor and sensory functions. TAK 242 was effective in alleviating the disease in both preventive and reversal paradigms. Conclusion The study identified the critical contribution of TLR4-mediated macrophage activation in disease course and provided strong evidence to support TLR4 as a useful drug target for treating inflammatory autoimmune neuropathy.

scholarly journals Inhibition of TLR4 Signaling Protects Mice From Sensory and Motor Dysfunction in an Animal Model of Autoimmune Peripheral Neuropathy

2021 ◽  
Author(s):  
Oladayo Oladiran ◽  
Xiang Qun Shi ◽  
Mu Yang ◽  
Sylvie Fournier ◽  
Ji Zhang
Keyword(s):  
Peripheral Neuropathy ◽  
T Cell Activation ◽  
Peripheral Nerves ◽  
Drug Target ◽  
Cell Activation ◽  
Disease Onset ◽  
Intraperitoneal Administration ◽  
Motor Dysfunction ◽  
Autoimmune Neuropathy ◽  
Molecular Patterns

Abstract BackgroundWhile the etiology remains elusive, macrophages and T cells in peripheral nerves are considered as effector cells mediating autoimmune peripheral neuropathy (APN), such as Guillain Barre Syndrome. By recognizing both pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) signals, TLRs play a central role in the initiation of both innate and adaptive immune responses. In this study, we aimed to understand the involvement of TLR4 in the pathogenesis of APN and explore the potential of TLR4 as a drug target for therapeutic use. MethodsAPN was induced by a partial ligation on one of the sciatic nerves in B7.2 (L31) transgenic mice which possess a predisposed inflammatory background. APN pathology and neurological function were evaluated on the other non-injured sciatic nerve. ResultsTLR4 and its endogenous ligand HMGB1 were highly expressed in L31 mice, in circulating immune cells and in peripheral nerves. Enhanced TLR4 signaling was blocked with TAK 242, a selective TLR4 inhibitor, before and after disease onset. Intraperitoneal administration of TAK 242 not only inhibited monocyte, macrophage and CD8 + T cell activation, but also reduced the release of pro-inflammatory cytokines. TAK 242 protected mice from severe myelin and axonal loss, resulting in a remarkable improvement in mouse motor and sensory functions. TAK 242 was effective in alleviating the disease in both preventive and reversal paradigms. ConclusionThe study identified the critical contribution of TLR4-mediated macrophage activation in disease course and provided strong evidence to support TLR4 as a useful drug target for treating inflammatory autoimmune neuropathy.

scholarly journals Modification of the Disease Progression in Mice with Experimental Autoimmune Encephalomyelitis Using Anti-Mitotic Compounds

2021 ◽  
Author(s):  
◽  
Kevin Patrick Crume
Keyword(s):  
Nitric Oxide ◽  
T Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Disease Onset ◽  
Autoimmune Response ◽  
Peloruside A ◽  
Proliferating Cells ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

<p>Multiple sclerosis (MS) is a multi-faceted disease, and is believed to be caused by an autoimmune response to myelin antigens in the central nervous system. Experimental autoimmune encephalomyelitis (EAE), an animal model for MS. manifests itself in various forms that parallel many aspects of MS, including the appearance of symptoms, initiation events, and pathophysiology. The hallmark of any immune response is the antigen-specific proliferation of immune cells, and during the initiation events of EAE, proliferating CD4+ T cells are the primary mediators of disease. This thesis explores if targeting these proliferating cells with the anti-mitotic compounds paclitaxel and peloruside A can delay or prevent the unset of EAE, thus providing a novel therapeutic avenue for MS research. The anti-cancer compound, paclitaxel, is an anti-mitotic drug that prevents microtubule depolymerisation. Although paclitaxel has been used in the clinical setting to treat cancer for over a decade, it has been determined that paclitaxel stimulates murine toll-like receptor 4 (TLR4) complex, which is the major LPS receptor. A novel microtubule-stabilising compound, peloruside, is currently subject to intensive investigations due to its functional similarity to paclitaxel. The results from this project found that peloruside and paclitaxel inhibited the proliferation of mitogen-stimulated splenocytes with IC50 values of 83 nM and 30 nM, respectively, but did not affect the viability of non-proliferating cells In contrast to paclitaxel, peloruside did not cause the TLR4-mediated production of the inflammatory mediators. TNF-epsilon, IL-12, and nitric oxide, when cultured with IFN-epsilon stimulated murine macrophages. Interestingly, when LPS was included with either paclitaxel or peloruside A, both drugs decreased the production of TNF-e and nitric oxide from macrophages, suggesting that microtubule-stabilising compounds may have anti-inflammatory effects. To identify any immunomodifying effects of paclitaxel in vivo, paclitaxel was administered to mice that were immunised with the myelin protein MOG in complete Freund's adjuvant (CFA) to induce EAE. When Taxol was administered to mice for 5 consecutive days immediately following CFA/MOG immunisation, the onset of EAE was delayed by approximately I week. Moreover, the administration of peloruside following the same treatment regime also resulted in a similar delay of disease onset. Taxol treatments, however, lead to significant mortality in immunised, but not unimmunised mice. Interestingly, although Taxol is an anti-mitotic drug, the proliferation of antigen-specific T cells was not inhibited in vivo by the Taxol treatment. The findings revealed in this thesis present an opportunity to pursue a new avenue of research for the therapeutic treatment of MS sufferers, and possibly other inflammatory autoimmune disorders.</p>

T Cells: A Growing Universe of Roles in Neurodegenerative Diseases

2021 ◽  
pp. 107385842110249
Author(s):  
Dallin Dressman ◽  
Wassim Elyaman
Keyword(s):  
T Cells ◽  
T Cell ◽  
Neurodegenerative Diseases ◽  
Human Leukocyte ◽  
Autoimmune Response ◽  
Antigen Specificity ◽  
Risk Genes ◽  
Leukocyte Antigen ◽  
Histocompatibility Complex ◽  
The Central Nervous System

T cells play a central role in homeostasis and host defense against infectious diseases. T cell dysregulation can lead to recognizing self-antigens as foreign antigens, causing a detrimental autoimmune response. T cell involvement in multiple sclerosis (MS), long understood to be an autoimmune-mediated neurodegenerative disease, is well characterized. More recently, a role for T cells has also been identified for the neurodegenerative diseases Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). Interestingly, several alleles and variants of human leukocyte antigen (HLA) genes have been classified as AD and PD risk genes. HLA codes for components of major histocompatibility complex (MHC) class I or class II, both of which are expressed by microglia, the innate immune cells of the central nervous system (CNS). Thus, both microglia and T cells may potentially interact in an antigen-dependent or independent fashion to shape the inflammatory cascade occurring in neurodegenerative diseases. Dissecting the antigen specificity of T cells may lead to new options for disease-modifying treatments in neurodegenerative diseases. Here, we review the current understanding of T cells in neurodegenerative diseases. We summarize the subsets of T cells, their phenotype and potential functions in animal models and in human studies of neurodegenerative diseases.

scholarly journals Enhancing the Nrf2 Antioxidant Signaling Provides Protection Against Trichloroethene-mediated Inflammation and Autoimmune Response

2020 ◽  
Vol 175 (1) ◽  
pp. 64-74 ◽  
Author(s):  
Nivedita Banerjee ◽  
Hui Wang ◽  
Gangduo Wang ◽  
M Firoze Khan
Keyword(s):  
Oxidative Stress ◽  
T Cells ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Autoimmune Response ◽  
Mediated Effects ◽  
Antioxidant Gene Expression ◽  
Responsive Element

Abstract Trichloroethene (trichloroethylene, TCE) and one of its reactive metabolites dichloroacetyl chloride (DCAC) are associated with the induction of autoimmunity in MRL+/+ mice. Although oxidative stress plays a major role in TCE-/DCAC-mediated autoimmunity, the underlying molecular mechanisms still need to be delineated. Nuclear factor (erythroid-derived 2)-like2 (Nrf2) is an oxidative stress-responsive transcription factor that binds to antioxidant responsive element (ARE) and provides protection by regulating cytoprotective and antioxidant gene expression. However, the potential of Nrf2 in the regulation of TCE-/DCAC-mediated autoimmunity is not known. This study thus focused on establishing the role of Nrf2 and consequent inflammatory responses in TCE-/DCAC-mediated autoimmunity. To achieve this, we pretreated Kupffer cells (KCs) or T cells with/without tert-butylhydroquinone (tBHQ) followed by treatment with DCAC. In both KCs and T cells, DCAC treatment significantly downregulated Nrf2 and HO-1 expression along with induction of Keap-1 and caspase-3, NF-κB (p65), TNF-α, and iNOS, whereas pretreatment of these cells with tBHQ attenuated these responses. The in vitro findings were further verified in vivo by treating female MRL+/+ mice with TCE along with/without sulforaphane. TCE exposure in mice also led to reduction in Nrf2 and HO-1 but increased phospho-NF-κB (p-p65) and iNOS along with increased anti-dsDNA antibodies. Interestingly, sulforaphane treatment led to amelioration of TCE-mediated effects, resulting in Nrf2 activation and reduction in inflammatory and autoimmune responses. Our results show that TCE/DCAC mediates an impairment in Nrf2 regulation. Attenuation of TCE-mediated autoimmunity via activation of Nrf2 supports that antioxidants sulforaphane/tBHQ could be potential therapeutic agents for autoimmune diseases.

scholarly journals Increased Density of Human Immunodeficiency Virus Type 1 Coreceptors CCR5 and CXCR4 on the Surfaces of CD4+ T Cells and Monocytes of Patients with Schistosoma mansoni Infection

2003 ◽  
Vol 71 (11) ◽  
pp. 6668-6671 ◽  
Author(s):  
W. Evan Secor ◽  
Amil Shah ◽  
Pauline M. N. Mwinzi ◽  
Bryson A. Ndenga ◽  
Caroline O. Watta ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Cell Surface ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Peripheral Blood ◽  
Chemokine Receptors ◽  
Blood Samples ◽  
Immunodeficiency Virus

ABSTRACT Distribution of chemokine receptors CCR5 and CXCR4, which are also coreceptors for human immunodeficiency virus type 1 invasion of cells, was measured on the surfaces of CD4+ T cells and monocytes in peripheral blood samples from a group of Kenyan car washers. Patients with active schistosomiasis displayed higher cell surface densities of these receptors than did cured schistosomiasis patients.

scholarly journals Degenerate TCR recognition and dual DR2 restriction of autoreactive T cells: Implications for the initiation of the autoimmune response in multiple sclerosis

2008 ◽  
Vol 38 (5) ◽  
pp. 1297-1309 ◽  
Author(s):  
Xin Zhang ◽  
Yunan Tang ◽  
Danuta Sujkowska ◽  
Jinzhao Wang ◽  
Vinod Ramgolam ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Autoimmune Response ◽  
Autoreactive T Cells

scholarly journals Characteristics of Regulatory T cells

2016 ◽  
Vol 85 (4) ◽  
pp. 323-326
Author(s):  
Magdalena Frydrychowicz ◽  
Maciej Boruczkowski ◽  
Agata Kolecka-Bednarczyk ◽  
Renata Jenek ◽  
Joanna Rosołowska ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Regulatory T Cells ◽  
Adhesion Molecules ◽  
Chemokine Receptors ◽  
Toll Like Receptors ◽  
Effector Cells

Regulatory T cells (Tregs) is heterogenic subpopulation of T cells that is able to suppress function of effector cells during the immune response. Among them are natural (nTreg) and induced Treg (Tr1, Th3, CD4+CD25-). CD25, CD45Ro, CD152, GITR, LAG-3, several adhesion molecules, chemokine receptors as well as Toll-like receptors are present on the surface of Treg. Mechanism of suppression used by nTreg is not completely understood.

Sign in / Sign up

Export Citation Format

Share Document