The JAK/STAT pathway in neuroinflammatory diseases.

摘要

Dysregulation of the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway is critically involved in the pathogenesis of multiple sclerosis (MS)/experimental autoimmune encephalomyelitis (EAE). Suppressor Of Cytokine Signaling (SOCS) proteins are the negative regulators of the JAK/STAT pathway. To determine the role of SOCS3 in myeloid cells in EAE, mice with conditional SOCS3 deletion in myeloid cells (LysMCre-SOCS3 fl/fl) were created and tested. LysMCre-SOCS3fl/fl mice develop a severe, non-resolving atypical form of disease, characterized by lesions and extensive neutrophil and other inflammatory cell infiltrates in the cerebellum and brainstem, elevated STAT activation, elevated cytokine, chemokine and iNOS expression, and prominent axonal damage. Mechanistically, loss of SOCS3 leads to a pronounced polarization to the pro-inflammatory macrophage (M1) phenotype, which promotes T-cell proliferation and polarization to Th1 and Th17 phenotypes, and has functional consequences for neurons. Cerebellum- and brainstem-infiltrating SOCS3-deficient neutrophils play a critical role in mediating atypical EAE development. Antibody-mediated depletion of neutrophils and blocking CXCR2 signaling ameliorates atypical EAE development. Functionally, SOCS3-deficient neutrophils produce high levels of CXCL2, CCL2, CXCL10, nitric oxide (NO), TNF-fNalpha and IL-1fbeta, recruiting themselves and other inflammatory infiltrates into the cerebellum and brainstem and creating a pro-inflammatory environment. Importantly, neutrophils may have a direct pathogenic role in driving axonal damage by local production of NO.;Dysregulation of the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway is critically involved in the pathogenesis of multiple sclerosis (MS)/experimental autoimmune encephalomyelitis (EAE). Suppressor Of Cytokine Signaling (SOCS) proteins are the negative regulators of the JAK/STAT pathway. To determine the role of SOCS3 in myeloid cells in EAE, mice with conditional SOCS3 deletion in myeloid cells (LysMCre-SOCS3 fl/fl) were created and tested. LysMCre-SOCS3fl/fl mice develop a severe, non-resolving atypical form of disease, characterized by lesions and extensive neutrophil and other inflammatory cell infiltrates in the cerebellum and brainstem, elevated STAT activation, elevated cytokine, chemokine and iNOS expression, and prominent axonal damage. Mechanistically, loss of SOCS3 leads to a pronounced polarization to the pro-inflammatory macrophage (M1) phenotype, which promotes T-cell proliferation and polarization to Th1 and Th17 phenotypes, and has functional consequences for neurons. Cerebellum- and brainstem-infiltrating SOCS3-deficient neutrophils play a critical role in mediating atypical EAE development. Antibody-mediated depletion of neutrophils and blocking CXCR2 signaling ameliorates atypical EAE development. Functionally, SOCS3-deficient neutrophils produce high levels of CXCL2, CCL2, CXCL10, nitric oxide (NO), TNF-falpha and IL-1fbeta, recruiting themselves and other inflammatory infiltrates into the cerebellum and brainstem and creating a pro-inflammatory environment. Importantly, neutrophils may have a direct pathogenic role in driving axonal damage by local production of NO.;As dysregulation of the JAK/STAT pathway has been implicated in MS/EAE, we utilized AZD1480, a JAK1/2 small molecule inhibitor, to investigate its therapeutic potential in models of EAE. Inhibition of JAK1/2 restrains pro-inflammatory responses in both T cells and myeloid cells. AZD1480 treatment suppresses differentiation of Th1 and Th17 cells and exerts an inhibitory effect on M1 polarization. Using AZD1480 for proof-of-principle, we demonstrate that inhibiting the JAK/STAT pathway has striking clinical efficacy in five EAE models: classical EAE, atypical EAE, relapsing-remitting (RR)-EAE, Th1 cell-mediated EAE, and Th17 cell-mediated EAE.;In conclusion, these studies reveal a role for SOCS3 in myeloid cells to provide protection against detrimental inflammatory responses in the central nervous system. In addition, our data suggest the feasibility of the JAK/STAT pathway as a therapeutic target for neuroinflammatory diseases.