Suppressor of cytokine signalling 3 (SOCS3) expressed in podocytes attenuates glomerulonephritis and suppresses autoantibody production in an imiquimod-induced lupus model

Objective Recently, podocytes have been recognised not only as a physical barrier to prevent urinary protein loss but also as producers of proinflammatory cytokines. However, the roles of podocytes in the pathogenesis of lupus nephritis (LN) remain largely unknown. This study aims to determine the roles of suppressor of cytokine signalling (SOCS) family members expressed in glomeruli in the regulation of LN.Methods We investigated the expression of SOCS family members in glomeruli in murine lupus model induced by repeated epicutaneous administration of the TLR7/8 agonist imiquimod. We also investigated the roles of SOCS3 expressed in podocytes in the imiquimod-induced glomerulonephritis and systemic autoimmunity by using podocyte-specific SOCS3-deficient mice (podocin-Cre x SOCS3fl/fl mice (SOCS3-cKO mice)). Finally, we investigated the expression of proinflammatory cytokines and chemokines in SOCS3-deficient podocyte cell lines.Results qPCR analysis revealed that among SOCS family members, SOCS3 was preferentially induced in glomeruli on epicutaneous administration of imiquimod and that interleukin 6 (IL-6) induced SOCS3 expression in podocyte cell lines. SOCS3-cKO mice exhibited severe glomerulonephritis, high levels of serum creatinine and urine albumin and decreased survival rate compared with control SOCS3-WT mice. Levels of anti-double-strand DNA antibody, SOCS (GC) formation and the numbers of follicular helper T (Tfh) cells and GC B cells in the spleen were higher in SOCS3-cKO mice than those in SOCS3-WT mice. Serum IL-6 levels and expression of IL-6 mRNA in glomeruli were also elevated in SOCS3-cKO mice. IL-6-induced IL-6 expression was enhanced in SOCS3-deficient podocyte cell lines compared with that in SOCS3-sufficient podocyte cell lines.Conclusion SOCS3 expressed in podocytes plays protective roles for the development of glomerulonephritis and inhibits autoantibody production in the imiquimod-induced lupus model presumably by suppressing IL-6 production of podocytes