Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0014070 (encephalomyelitis)
 13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiple sclerosis is considered to be initiated by a deregulated, myelin-specific T cell response. However, the formation of inflammatory CNS lesions and the contribution of different leukocyte subsets in setting up these lesions are still incompletely understood. In this study, we show that, in the mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis, neutrophil granulocytes are important contributors in preparing CNS inflammation. Preclinical single-dose Ab-mediated depletion of neutrophils delayed the onset and continuous depletion attenuated the development of experimental autoimmune encephalomyelitis, whereas the generation of a myelin-specific T cell response remained unaffected. Neutrophil-related enzymes such as myeloperoxidase and neutrophil elastase did not contribute in mounting CNS inflammation, as analyzed by using respective knockout mice and inhibitors. CNS-infiltrating neutrophils secreted proinflammatory molecules and matured bone marrow-derived dendritic cells in vitro, which in turn enhanced their ability to restimulate myelin-specific T cells. This was mirrored in vivo, in which depletion of neutrophils specifically impaired maturation of microglia and macrophages into professional APCs, resulting in a diminished amplification of early CNS inflammation. Therefore, inside the CNS neutrophils provide local cofactors that are required for the maturation of myeloid cells into professional APCs representing an essential step for the local restimulation of myelin-specific T cells and the development of autoimmune disease.
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PMID:Neutrophils amplify autoimmune central nervous system infiltrates by maturing local APCs. 2406 88

A major function of T helper (Th) 17 cells is to induce the production of factors that activate and mobilize neutrophils. Although Th17 cells have been implicated in the pathogenesis of multiple sclerosis (MS) and the animal model experimental autoimmune encephalomyelitis (EAE), little attention has been focused on the role of granulocytes in those disorders. We show that neutrophils, as well as monocytes, expand in the bone marrow and accumulate in the circulation before the clinical onset of EAE, in response to systemic up-regulation of granulocyte colony-stimulating factor (G-CSF) and the ELR(+) CXC chemokine CXCL1. Neutrophils comprised a relatively high percentage of leukocytes infiltrating the central nervous system (CNS) early in disease development. G-CSF receptor deficiency and CXCL1 blockade suppressed myeloid cell accumulation in the blood and ameliorated the clinical course of mice that were injected with myelin-reactive Th17 cells. In relapsing MS patients, plasma levels of CXCL5, another ELR(+) CXC chemokine, were elevated during acute lesion formation. Systemic expression of CXCL1, CXCL5, and neutrophil elastase correlated with measures of MS lesion burden and clinical disability. Based on these results, we advocate that neutrophil-related molecules be further investigated as novel biomarkers and therapeutic targets in MS.
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PMID:Neutrophil-related factors as biomarkers in EAE and MS. 2555 93

Pain is a frequent and disabling symptom in patients with multiple sclerosis (MS); however, the underlying mechanisms of MS-related pain are not fully understood. Here, we demonstrated that cathepsin E (CatE) in neutrophils contributes to the generation of mechanical allodynia in experimental autoimmune encephalomyelitis, an animal model of MS. We showed that CatE-deficient (CatE) mice were highly resistant to myelin oligodendrocyte glycoprotein (MOG35-55)-induced mechanical allodynia. After MOG35-55 immunization, neutrophils immediately accumulated in the dorsal root ganglion (DRG). Adoptive transfer of MOG35-55-stimulated wild-type neutrophils into the dorsal root ganglion induced mechanical allodynia in the recipient C57BL/6 mice. However, the pain threshold did not change when MOG35-55-stimulated CatE neutrophils were transferred into the recipient C57BL/6 mice. MOG35-55 stimulation caused CatE-dependent secretion of elastase in neutrophils. Behavioral analyses revealed that sivelestat, a selective neutrophil elastase inhibitor, suppressed mechanical allodynia induced by adoptively transferred MOG35-55-stimulated neutrophils. MOG35-55 directly bound to toll-like receptor 4, which led to increased production of CatE in neutrophils. Our findings suggest that inhibition of CatE-dependent elastase production in neutrophil might be a potential therapeutic target for pain in patients with MS.
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PMID:Cathepsin E in neutrophils contributes to the generation of neuropathic pain in experimental autoimmune encephalomyelitis. 3109 99

Multiple sclerosis (MS) is a potentially disabling disease of the central nervous system. Approximately half of the patients with MS experience severe pain; however, currently available therapeutics provide only insufficient relief. The mechanisms underlying the generation of neuropathic pain in patients with MS are not fully understood. Recently, we found that neutrophil elastase from accumulated neutrophils in the dorsal root ganglion (DRG) sensitizes DRG neurons and induces mechanical allodynia in a mouse model of experimental autoimmune encephalomyelitis (EAE). However, the mechanism underlying neutrophil accumulation in the DRG after myelin oligodendrocyte glycoprotein (MOG35-55, immunogenic peptide) immunization remains unclear. Here, we found that C-X-C motif ligand 1 (CXCL1) was upregulated in DRG neurons after MOG35-55 immunization. Increased expression of CXCL1 protein was also observed in primary cultured DRG neurons treated with MOG35-55, which was mediated through toll-like receptor 4 (TLR4). Gene silencing of TLR4 or CXCL1 in DRG neurons significantly attenuated neutrophil accumulation in the DRG and mechanical allodynia during the preclinical phase of EAE (around day 5 after immunization). Our results thus suggest that a TLR4-CXCL1 pathway in DRG neurons triggers neutrophil recruitment in the DRG and subsequent mechanical allodynia in response to MOG35-55.
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PMID:A TLR-CXCL1 pathway in DRG neurons induces neutrophil accumulation in the DRG and mechanical allodynia in EAE mice. 3142 56