O016 Inhibition of the JAK/STAT pathway protects against neuroinflammation

Abstract

Introduction Suppressor Of Cytokine Signaling (SOCS) proteins are feedback inhibitors of the JAK/STAT pathway. SOCS3 has a crucial role in inhibiting STAT activation, cytokine signaling and inflammatory gene expression in macrophages/microglia. Methods To determine the role of SOCS3 in myeloid cells in neuroinflammation, mice with conditional SOCS3 deletion in myeloid cells (LysMCre-SOCS3fl/fl) were tested for experimental autoimmune encephalomyelitis (EAE). Results The myeloid specific SOCS3-deficient mice are vulnerable to MOG-induced EAE, with a severe, non-resolving atypical form of disease. In vivo, enhanced infiltration of inflammatory cells and demyelination is prominent in the cerebellum of myeloid specific SOCS3-deficient mice, as is enhanced STAT3/4 signaling and expression of inflammatory cytokines/chemokines, and an immune response dominated by Th1 and Th17 cells. In vitro, SOCS3-deficient macrophages exhibit heightened STAT3 activation, and are polarized toward the classical M1 phenotype. SOCS3-deficient M1 macrophages provide the microenvironment to polarize Th1 and Th17 cells and induce neuronal death. Furthermore, adoptive transfer of anti-inflammatory M2 macrophages into myeloid SOCS3-deficient mice leads to delayed onset and reduced severity of atypical EAE by decreasing STAT3 activation, Th1/Th17 cells and proinflammatory mediators in the cerebellum. These findings indicate that myeloid cell SOCS3 provides protection from EAE through deactivation of neuroinflammatory responses. LysMCre-SOCS3fl/fl mice are also protected from atypical EAE by the administration of a JAK/STAT3 inhibitor, AZD1480. Severity of disease is attenuated, which is associated with a reduction in STAT1/3 activation, less Th1/Th17 cell infiltration in the cerebellum, reductions in inflitrating neutrophils and macrophages, and decreased M1 proinflammatory gene expression. Mice with classical EAE are also protected against disease severity by treatment with AZD1480. Conclusion Collectively, these findings indicate the JAK/STAT3 signaling pathway may serve as a therapeutic target for neuroinflammatory diseases.