The role of IL-25 in the development of murine lupus

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple organ inflammatory damage and aberrant production of autoantibodies. Numerous studies have demonstrated significant roles of IL-17 and Th17 cells in the development of SLE. However, the roles of IL-25 (also named IL-17E), an important member of the IL-17 family cytokines, in the pathogenesis of SLE remain largely unclear. This study aims to investigate the role of IL-25 and elucidate the underlying effector mechanisms in the development of murine lupus. In SLE patients, the concentrations of IL-25 in serum were markedly elevated compared with healthy donors and positively correlated with the SLE disease activity index (SLEDAI). Moreover, a murine lupus model was successfully established, which recapitulates the hallmark features of SLE patients, including renal damage, the presence of various autoantibodies, and excessive inflammatory responses. In chromatin-induced lupus mice, the levels of IL-25 in serum and kidney tissues were significantly increased compared with normal mice. To investigate the role of IL-25 in lupus pathogenesis, wild-type (WT) and IL-25 knockout (KO) mice were immunized for lupus induction. Compared with WT counterparts, IL-25 KO mice exhibited significantly increased levels of autoantibodies and creatinine in serum as well as proteins in urine. Moreover, the histopathological analysis showed more severe renal tissue damage as evidenced by exacerbated kidney tissue inflammation and glomerular damage in IL-25 KO mice, suggesting that IL-25 protected lupus development in mice. Immune cell profiling revealed enhanced Th17 responses with increased numbers of GM-CSF+ pathogenic Th17 (pTh17) subsets in mice with IL-25 deficiency. In culture, IL-25 significantly suppressed differentiation of both mouse and human Th17 cells. Moreover, IL-25 decreased the expression of IL-23R and IL-1R, two key markers for pTh17 cells. To elucidate the metabolic and molecular mechanism by which IL-25 regulates Th17 differentiation, cultured Th17 cells with and without IL-25 treatments were collected for a glycolysis stress test. IL-25 significantly decreased glycolysis levels in Th17 cells, together with reduced expression of glucose transporter 1 (GLUT1) and decreased glucose uptake. Gene expression analysis showed that IL-25 decreased the expression of many glycolysis-associated genes. In addition, IL-25 suppressed the expression of HIF-1α, a key glycolytic regulator. Mechanistically, IL-25 treatment inhibited phosphorylation of STAT3 and activation of AKT1-mTOR pathway, both of which play a critical role in modulating HIF-1α expression, glycolytic metabolism and Th17 responses.

Currently, effective therapies for SLE patients are still lacking. In this study, recombinant IL-25 was shown to effectively ameliorate lupus development in mice. The lupus mice exhibited reduced levels of proteinuria and serum creatinine upon IL-25 treatment. Histological assessments revealed that IL-25 administration markedly attenuated kidney damage. Moreover, IL-25 treatment significantly suppressed lupus development in a humanized lupus model established in NOD scid gamma (NSG) mice. Taken together, these findings have revealed a regulatory role of IL-25 in lupus development by suppressing Th17 cell glycolysis and differentiation. Moreover, the preclinical study has identified IL-25 as a promising strategy for treating lupus in mice, which may contribute to the development of novel effective therapies for treating SLE patients.