IFN-γ promotes the development of systemic lupus erythematosus through the IFNGR1/2-PSTAT1-TBX21 signaling axis.

Background: Systemic lupus erythematosus (SLE) is a chronic disease that causes inflammation in cartilage and the lining of blood vessels. Emerging evidence implicates IFN-γ as a major effector molecule in SLE during both active and stable stages. Here, we investigated the effects of IFN-γ on cytokines that play an autoimmune disease-promoting role and Th1-versus-Th2 and B cell dualism in SLE patients and mouse models of SLE.

Methods: The levels of pro-inflammatory factors CXCL11, IFN-γ, IL-1β and IL-4, and immune complexes IgG, anti-dsDNA and anti-RNP were assessed through enzyme-linked immunosorbent assays (ELISA). Flow cytometry was performed to measure Th1, Th2 and B cell counts and IFNGR1, IFNGR2, pSTAT1 and TBX21 expression. The pathology of renal tissue from mouse SLE models was investigated through Hematoxylin eosin (H&E) staining. The levels of IgG, anti-dsDNA and anti-RNP were determined through immunofluorescence (IF) assays.

Results: Skin damage was observed in SLE patients in both active and stable stages. ELISA analysis showed that SLE patients displayed higher levels of pro-inflammatory factors (CXCL11, IFN-γ, IL-1β and IL-4) and immune complexes (IgG, anti-dsDNA and anti-RNP). The percentage of Th1 and B cells was increased in blood samples from SLE patients with skin lesions (SL) or lupus nephritis (LN). The percentage of Th2 cells among the groups were comparable. Higher levels of IFNGR1, IFNGR2, pSTAT1 and TBX21 were observed in Th1 but not Th2 cells. In SLE mouse models, H&E staining revealed fewer immune complexes in glomerular endothelial cells and decreased hyaline thrombus in the capillary lumen following treatment with anti-IFN-γ antibodies or following IFNGR1 or STAT1 silencing.

Conclusion: IFN-γ contributes to the pathogenesis of SLE through the IFNGR1/2-pSTAT1-TBX21 axis and regulates inflammation and immune complex formation in SLE mice.