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Platelets contribute to the pathogenesis of experimental autoimmune encephalomyelitis.

ABSTRACT: RATIONALE:Multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE), are inflammatory disorders of the central nervous system (CNS). The function of platelets in inflammatory and autoimmune pathologies is thus far poorly defined. OBJECTIVE:We addressed the role of platelets in mediating CNS inflammation in EAE. METHODS AND RESULTS:We found that platelets were present in human MS lesions as well as in the CNS of mice subjected to EAE but not in the CNS from control nondiseased mice. Platelet depletion at the effector-inflammatory phase of EAE in mice resulted in significantly ameliorated disease development and progression. EAE suppression on platelet depletion was associated with reduced recruitment of leukocytes to the inflamed CNS, as assessed by intravital microscopy, and with a blunted inflammatory response. The platelet-specific receptor glycoprotein Ib? (GPIb?) promotes both platelet adhesion and inflammatory actions of platelets and targeting of GPIb? attenuated EAE in mice. Moreover, targeting another platelet adhesion receptor, glycoprotein IIb/IIIa (GPIIb/IIIa), also reduced EAE severity in mice. CONCLUSIONS:Platelets contribute to the pathogenesis of EAE by promoting CNS inflammation. Targeting platelets may therefore represent an important new therapeutic approach for MS treatment.

SUBMITTER: Langer HF

PROVIDER: S-EPMC3382058 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Platelets contribute to the pathogenesis of experimental autoimmune encephalomyelitis.

Langer Harald F HF Choi Eun Young EY Zhou Hong H Schleicher Rebecca R Chung Kyoung-Jin KJ Tang Zhongshu Z Göbel Kerstin K Bdeir Khalil K Chatzigeorgiou Antonios A Wong Connie C Bhatia Sumeena S Kruhlak Michael J MJ Rose John W JW Burns James B JB Hill Kenneth E KE Qu Hongchang H Zhang Yongqing Y Lehrmann Elin E Becker Kevin G KG Wang Yunmei Y Simon Daniel I DI Nieswandt Bernhard B Lambris John D JD Li Xuri X Meuth Sven G SG Kubes Paul P Chavakis Triantafyllos T

Circulation research 20120327 9

<h4>Rationale</h4>Multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE), are inflammatory disorders of the central nervous system (CNS). The function of platelets in inflammatory and autoimmune pathologies is thus far poorly defined.<h4>Objective</h4>We addressed the role of platelets in mediating CNS inflammation in EAE.<h4>Methods and results</h4>We found that platelets were present in human MS lesions as well as in the CNS of mice subjected to EAE but no ...[more]

PMID: 22456181

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Project description:BackgroundInterleukin 9 (IL-9), produced mainly by T helper 9 (Th9) cells, has been recognized as an important regulator in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Astrocytes respond to IL-9 and reactive astrocytes always associate with blood-brain barrier damage, immune cell infiltration, and spinal injury in MS and EAE. Several long non-coding RNAs (lncRNAs) with aberrant expression have been identified in the pathogenesis of MS. Here, we examined the effects of lncRNA Gm13568 (a co-upregulated lncRNA both in EAE mice and in mouse primary astrocytes activated by IL-9) on the activation of astrocytes and the process of EAE.MethodsIn vitro, shRNA-recombinant lentivirus with glial fibrillary acidic protein (GFAP) promoter were performed to determine the relative gene expression and proinflammatory cytokines production in IL-9 treated-astrocytes using Western blot, real-time PCR, and Cytometric Bead Array, respectively. RIP and ChIP assays were analyzed for the mechanism of lncRNA Gm13568 regulating gene expression. Immunofluorescence assays was performed to measure the protein expression in astrocytes. In vivo, H&E staining and LFB staining were applied to detect the inflammatory cells infiltrations and the medullary sheath damage in spinal cords of EAE mice infected by the recombinant lentivirus. Results were analyzed by one-way ANOVA or Student's t test, as appropriate.ResultsKnockdown of the endogenous lncRNA Gm13568 remarkably inhibits the Notch1 expression, astrocytosis, and the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) as well as the production of inflammatory cytokines and chemokines (IL-6, TNF-α, IP-10) in IL-9-activated astrocytes, in which Gm13568 associates with the transcriptional co-activators CBP/P300 which are enriched in the promoter of Notch1 genes. More importantly, inhibiting Gm13568 with lentiviral vector in astrocytes ameliorates significantly inflammation and demyelination in EAE mice, therefore delaying the EAE process.ConclusionsThese findings uncover that Gm13568 regulates the production of inflammatory cytokines in active astrocytes and affects the pathogenesis of EAE through the Notch1/STAT3 pathway. LncRNA Gm13568 may be a promising target for treating MS and demyelinating diseases.

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Platelets contribute to the pathogenesis of experimental autoimmune encephalomyelitis.

Publications

Platelets contribute to the pathogenesis of experimental autoimmune encephalomyelitis.

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