Signal transducer and activator of transcription-3/suppressor of cytokine signaling-3 (STAT3/SOCS3) axis in myeloid cells regulates neuroinflammation

Abstract

Suppressor of cytokine signaling (SOCS) proteins are feedback inhibitors of the JAK/STAT pathway. SOCS3 has a crucial role in inhibiting STAT3 activation, cytokine signaling, and inflammatory gene expression in macrophages/microglia. 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). The myeloid-specific SOCS3-deficient mice are vulnerable to myelin oligodendrocyte glycoprotein (MOG)-induced EAE, with a severe, nonresolving 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 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 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. Th1 cells | M1 polarization

Preferential Recruitment of Neutrophils into the Cerebellum and Brainstem Contributes to the Atypical Experimental Autoimmune Encephalomyelitis Phenotype

“…We previously demonstrated that mice with a specific deletion of the suppressor of cytokine signaling 3 (SOCS3) gene in myeloid cells (LysMCre-SOCS3 fl/fl ) develop early onset of a severe and nonresolving disease with features of atypical EAE, which is characterized by involvement of the CRB, rather than the SC, and ataxia, significant weight loss, axial rotation, and tremors (3). Importantly, we found that there was a striking neutrophil infiltration in the brain.…”

“…Active EAE was induced as previously described (3,34). Eight-to 12-wkold SOCS3 fl/fl or LysMCre-SOCS3 fl/fl mice were immunized s.c. with 100 mg MOG emulsified in CFA (supplemented with 2 mg/ml Mycobacterium tuberculosis) and injected i.p.…”

“…at the indicated time points. Mice were sacrificed and perfused, and mononuclear cells were isolated from the CNS (CRB, BS, and SC) by a 30/70% Percoll gradient, or from draining cervical lymph nodes and spleen (SP), and cell phenotype was determined by surface and intracellular staining by flow cytometry, as previously described (3,34).…”

“…It is now appreciated that myeloid cells, including dendritic cells, macrophages/monocytes, and activated microglia, as well as astrocytes, are important components of disease initiation and progression (2)(3)(4)(5)(6). Increasing evidence suggests an important role of neutrophils in MS/EAE.…”

JAK Inhibition: A new therapeutic strategy for management of chronic diseases

“…In particular, SOCS3 has been shown to bind and directly inhibit the catalytic domains of JAKs via an evolutionarily conserved motif. Taking advantage of this role, a preclinical study has revealed that expression of SOCS3 in myeloid cells provides protection through deactivation of neuroinflammatory responses [11]. In non-small cell lung cancer (NSCLC) tumor samples, expression of SOCS3 has been shown to be lost due to promoter hyper methylation, an epigenetic change that reduces gene transcription.…”