Macrophage Migration Inhibitory Factor deficiency attenuates kidney Injury by downregulating cytokines via CYR61 in lupus-prone mice induced by pristane.

Abstract Background Lupus nephritis (LN) is one of the most serious manifestations of systemic lupus erythematous (SLE) and accounts for significant mortality and morbidity. Previous research has demonstrated that macrophage migration inhibitory factor (MIF) is involved in the pathogenesis of lupus nephritis, but the detailed mechanism is not elucidated. The aim of this study was to explore the pathogenesis of MIF in lupus nephritis with the pristane-induced mouse model of SLE. Methods Mif-/- mice and Wild type mice in the C57BL/6 (B6) background were used to induce Lupus model by pristane. 24 hour urine and sera were collected in the sixth month and mice were sacrificed to harvest tissues. Serum ANA, anti-dsDNA antibodies, C3, urinary creatinine and albumin were detected by ELISA. Related inflammatory cytokines were detected by Bio-Plex Pro™ assays and ELISA. CYR61 mRNA expression was detected by RT-qPCR and CYR61 protein expression were detected by Western blot. Immunofluorescence was used to detect the expression of MIF, ICs and C3 deposition and related cytokines expression in the kidneys. Immunohistochemical staining was used to detect macrophage infiltration and periodic acid-Schiff (PAS) staining were used for kidney histology. The Mann-Whitney test and Student’s t test were used to compare multiple group differences. The correlation were analyzed by Spearman correlation. Results Mif -/- mice with pristane-induced SLE have less inflammatory cytokines expression in sera. The Mif-/- mice have reduced renal injury, less macrophage infiltration, CYR61 and inflammatory cytokines expression in the kidneys. MIF induced the expression of CYR61, which can induce the expression of IL-1β, IL-6 and MCP-1 in bone marrow-derived macrophages (BMDM) in a cell-based assay. Conclusions The results suggest that MIF plays an important role in kidney injury by inducing macrophages infiltration and inflammatory cytokines expression in situ. Our finding support the pathogenic contribution of high expression MIF alleles in SLE and suggest that MIF antagonism might offer an effective therapeutic option in lupus nephritis.