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 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 Lipidomics study of plasma from patients suggest that ALS and PLS are part of a continuum of motor neuron disorders

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Estela Area-Gomez ◽  
D. Larrea ◽  
T. Yun ◽  
Y. Xu ◽  
J. Hupf ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Cell Structure ◽  
Disease Onset ◽  
Point Of View ◽  
Motor Dysfunction ◽  
Cellular Processes ◽  
Progressive Muscle Weakness ◽  
Human Pathology ◽  
Lateral Sclerosis

AbstractMotor neuron disorders (MND) include a group of pathologies that affect upper and/or lower motor neurons. Among them, amyotrophic lateral sclerosis (ALS) is characterized by progressive muscle weakness, with fatal outcomes only in a few years after diagnosis. On the other hand, primary lateral sclerosis (PLS), a more benign form of MND that only affects upper motor neurons, results in life-long progressive motor dysfunction. Although the outcomes are quite different, ALS and PLS present with similar symptoms at disease onset, to the degree that both disorders could be considered part of a continuum. These similarities and the lack of reliable biomarkers often result in delays in accurate diagnosis and/or treatment. In the nervous system, lipids exert a wide variety of functions, including roles in cell structure, synaptic transmission, and multiple metabolic processes. Thus, the study of the absolute and relative concentrations of a subset of lipids in human pathology can shed light into these cellular processes and unravel alterations in one or more pathways. In here, we report the lipid composition of longitudinal plasma samples from ALS and PLS patients initially, and after 2 years following enrollment in a clinical study. Our analysis revealed common aspects of these pathologies suggesting that, from the lipidomics point of view, PLS and ALS behave as part of a continuum of motor neuron disorders.

scholarly journals Nodes, paranodes and neuropathies

2017 ◽  
Vol 89 (1) ◽  
pp. 61-71 ◽  
Author(s):  
Janev Fehmi ◽  
Steven S Scherer ◽  
Hugh J Willison ◽  
Simon Rinaldi
Keyword(s):  
Peripheral Nerves ◽  
Clinical Importance ◽  
Specific Cell ◽  
Peripheral Neuropathies ◽  
Autoimmune Neuropathy ◽  
Basic Understanding ◽  
Clinical Variants ◽  
Inflammatory Neuropathies ◽  
The Common ◽  
Treatment Responsiveness

This review summarises recent evidence supporting the involvement of the specialised nodal and perinodal domains (the paranode and juxtaparanode) of myelinated axons in the pathology of acquired, inflammatory, peripheral neuropathies.The identification of new target antigens in the inflammatory neuropathies heralds a revolution in diagnosis, and has already begun to inform increasingly targeted and individualised therapies. Rapid progress in our basic understanding of the highly specialised nodal regions of peripheral nerves serves to strengthen the links between their unique microstructural identities, functions and pathologies. In this context, the detection of autoantibodies directed against nodal and perinodal targets is likely to be of increasing clinical importance. Antiganglioside antibodies have long been used in clinical practice as diagnostic serum biomarkers, and associate with specific clinical variants but not to the common forms of either acute or chronic demyelinating autoimmune neuropathy. It is now apparent that antibodies directed against several region-specific cell adhesion molecules, including neurofascin, contactin and contactin-associated protein, can be linked to phenotypically distinct peripheral neuropathies. Importantly, the immunological characteristics of these antibodies facilitate the prediction of treatment responsiveness.

scholarly journals Diabetic peripheral neuropathy: epidemiology, pathogenesis, clinic, diagnostics, treatment

2016 ◽  
Vol 24 (4) ◽  
pp. 139-151 ◽  
Author(s):  
A N Belova ◽  
M N Kudykin ◽  
G E Sheiko
Keyword(s):  
Peripheral Neuropathy ◽  
Diabetic Peripheral Neuropathy ◽  
Peripheral Nerves ◽  
Pain Syndrome ◽  
Common Complication ◽  
Review Of Literature ◽  
Chronic Hyperglycemia ◽  
Progressive Degeneration ◽  
Pathophysiologic Mechanisms

The article contains the review of literature data dedicated to the most common complication associated with diabetes mellitus (DM) - the diabetic peripheral neuropathy (DPN). DPN is regarded as economic burden for any state and significantly influences the quality of patient’s life. DPN is characterized by progressive degeneration of peripheral nerves that leads to pain syndrome, movement disorders and loss of sensation. There is a set of theories of development of DPN, but the major etiological factor is the chronic hyperglycemia. The article describes pathophysiologic mechanisms of DPN development. It is noted that considering high variability of clinical pattern DPN has no unified classification. The article addresses issues related to diagnostics and criteria of establishing the diagnosis. Special attention of the article is dedicated to pathogenic and expected treatment methods.

scholarly journals Management of Peripheral Neuropathy and Cardiovascular Effects in Vitamin B12 Deficiency

2021 ◽  
Vol 10 (5) ◽  
Author(s):  
Nishant Kumar Singh ◽  
Hirni J. Patel ◽  
Mohit Buddhadev ◽  
S P Srinivas Nayak ◽  
Gunosindhu Chakraborthy
Keyword(s):  
Cardiovascular Disease ◽  
Peripheral Neuropathy ◽  
Vitamin B12 ◽  
Peripheral Nerves ◽  
Vitamin B12 Deficiency ◽  
Cardiovascular Effects ◽  
The Elderly ◽  
Vitamin Deficiencies ◽  
B12 Deficiency ◽  
Artery Disease

Peripheral nerves are susceptible to damage by a wide array of toxins, medications, and vitamin deficiencies. Vitamin B12 (VB12) deficiency neuropathy is a rare debilitating disease that affects mostly the elderly. It is important to consider these etiologies when approaching patients with a variety of neuropathic presentations in this review were have included most relevant and latest information on mechanisms causing Peripheral neuropathy in VB12 deficiency. We also have included cardiovascular disorders and their management. Hyperhomocysteinemia has been implicated in endothelial dysfunction and cardiovascular disease. The association of homocysteine (Hcy) and VB12 with cardiovascular risk factors in patients with coronary artery disease (CAD) has also been studied Keywords: Peripheral Neuropathy, Vitamin B12 Deficiency, Cardiovascular Disease and Homocysteine.

scholarly journals Preconditioning Enhances the Therapeutic Effects of Mesenchymal Stem Cells on Colitis Through PGE2-Mediated T-Cell Modulation

2018 ◽  
Vol 27 (9) ◽  
pp. 1352-1367 ◽  
Author(s):  
Fu Yuan Yang ◽  
Rui Chen ◽  
Xiaohu Zhang ◽  
Biao Huang ◽  
Lai Ling Tsang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Therapeutic Effect ◽  
T Cell Activation ◽  
Activity Index ◽  
Intraperitoneal Administration ◽  
The Body ◽  
Human Umbilical Cord ◽  
Therapeutic Effects ◽  
Anti Inflammatory

Mesenchymal stem cell (MSC)-based cell therapy has been demonstrated as a promising strategy in the treatment of inflammatory bowel disease (IBD), which is considered an immune disease. While the exact mechanisms underlying the therapeutic effect of MSCs are still unclear, MSCs display anti-inflammatory and immunomodulatory effects by interacting with various immunoregulatory cells. Our previous studies have shown that MSCs can be preconditioned and deconditioned with enhanced cell survival, differentiation and migration. In this study, we evaluated the effect of preconditioning on the immunoregulatory function of human umbilical cord-derived MSCs (hUCMSCs) and their therapeutic effect on treating IBD. Our results show that intraperitoneal administration of deconditioned hUCMSCs (De-hUCMSCs) reduces the disease activity index (DAI), histological colitis score and destruction of the epithelial barrier, and increases the body weight recovery more intensively than that of un-manipulated hUCMSCs. In addition, De-hUCMSCs but not hUCMSCs elicit anti-apoptotic effects via induction of the ERK pathway during the early stage of IBD development. In vitro co-culture studies indicate that De-hUCMSCs suppress T-cell proliferation and activation more markedly than hUCMSCs. Moreover, De-hUCMSCs block the induction of inflammatory cytokines such as tumor necrosis factor (TNF)α and interleukin (IL)-2, while promoting the secretion of the anti-inflammatory cytokine IL-10 in T-cells. Mechanically, we find that prostaglandin E2 (PGE2) secretion is significantly increased in De-hUCMSCs, the suppression of which dramatically abrogates the inhibitory effect of De-hUCMSCs on T-cell activation, implying that the crosstalk between De-hUCMSCs and T-cells is mediated by PGE2. Together, we have demonstrated that preconditioning enhances the immunosuppressive and therapeutic effects of hUCMSCs on treating IBD via increased secretion of PGE2.

Dysautonomia as Onset Symptom of Myotonic Dystrophy Type 2

2018 ◽  
Vol 79 (3-4) ◽  
pp. 166-170
Author(s):  
Salvatore Rossi ◽  
Angela Romano ◽  
Anna Modoni ◽  
Francesco Perna ◽  
Valentina Rizzo ◽  
...  
Keyword(s):  
Myotonic Dystrophy ◽  
Peripheral Nerves ◽  
Autosomal Dominant ◽  
Disease Onset ◽  
Clinical Signs ◽  
Myotonic Dystrophy Type ◽  
Multisystem Disorder ◽  
Myotonic Dystrophy Type 2 ◽  
Cctg Repeat

Myotonic dystrophy type 2 (DM2) is an autosomal dominant muscular dystrophy caused by the expansion of an intronic tetranucleotide CCTG repeat in CNBP on chromosome 3. As DM1, DM2 is a multisystem disorder affecting, beside the skeletal muscle, various other tissues, including peripheral nerves. Indeed, a subclinical involvement of peripheral nervous system has been described in several cohorts of DM2 patients, whereas DM2 patients manifesting clinical signs and/or symptoms of neuropathy have been only rarely reported. Here, we describe 2 related DM2 patients both of whom displayed an atypical disease onset characterized by dysautonomic symptoms, possibly secondary to peripheral neuropathy.

scholarly journals Treatment of Relapsing Paralysis in Experimental Encephalomyelitis by Targeting Th1 Cells through Atorvastatin

2003 ◽  
Vol 197 (6) ◽  
pp. 725-733 ◽  
Author(s):  
Orhan Aktas ◽  
Sonia Waiczies ◽  
Alina Smorodchenko ◽  
Jan Dörr ◽  
Bibiane Seeger ◽  
...  
Keyword(s):  
T Cell ◽  
Mhc Class Ii ◽  
T Cell Activation ◽  
Disease Onset ◽  
Class Ii ◽  
T Cell Response ◽  
In Vitro Assays ◽  
Inhibition Of Proliferation ◽  
Autoreactive T Cell ◽  
Autoimmune Attack

Statins, known as inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, exhibit numerous functions related to inflammation, such as MHC class II down-regulation, interference with T cell adhesion, and induction of apoptosis. Here we demonstrate that both subcutaneous and oral administration of atorvastatin inhibit the development of actively induced chronic experimental autoimmune encephalomyelitis in SJL/J mice and significantly reduce the inflammatory infiltration into the central nervous system (CNS). When treatment was started after disease onset, atorvastatin reduced the incidence of relapses and protected from the development of further disability. Both the reduced autoreactive T cell response measured by proliferation toward the encephalitogenic peptide PLP139–151 and the cytokine profile indicate a potent blockade of T helper cell type 1 immune response. In in vitro assays atorvastatin not only inhibited antigen-specific responses, but also decreased T cell proliferation mediated by direct TCR engagement independently of MHC class II and LFA-1. Inhibition of proliferation was not due to apoptosis induction, but linked to a negative regulation on cell cycle progression. However, early T cell activation was unaffected, as reflected by unaltered calcium fluxes. Thus, our results provide evidence for a beneficial role of statins in the treatment of autoimmune attack on the CNS.

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