030 IRF7 and IRF8 have distinct effects on the pathogenesis of systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by the loss of tolerance against nuclear autoantigens in which the production of autoantibodies leads to tissue damages through the formation and deposition of immune complexes. Recent genome-wide association studies of SLE patients have revealed that polymorphisms of interferon regulatory factor (IRF) 7 and IRF8 are associated with an increased risk of SLE but the precise role of these IRFs in SLE development is not fully understood. IRF7 and IRF8 belong to the IRF family of transcription factors that regulate transcription of type I Interferon (IFN) and the expression of IFN-stimulated genes. Using a murine model of SLE induced by 2,6,10,14-tetramethylpentadecane (TMPD), we previously reported that IRF7 knockout (KO) mice failed to produce autoantibodies such as anti-dsDNA, ssDNA, nRNP and Sm antibodies but developed glomerulonephritis. In contrast, we found that IRF8KO mice showed no production of autoantibodies along with reduced glomerulonephritis after TMPD injection. TMPD induced apoptosis similarly in wild-type (WT), IRF7KO, and IRF8KO mice, suggesting that the dysregulation of apoptosis was not involved in the pathogenesis of SLE-like symptoms in these mice. These results suggest that type I IFN pathway is critical for autoantibody production but not development of glomerulonephritis. In order to explore the mechanism responsible for tissue damage including glomerulonephritis in this experimental model of SLE, we analyzed the peritoneal cell infiltrate in these mice. We found that inflammatory monocytes were recruited into the peritoneum in WT and IRF7KO mice but not in IRF8KO mice 2 weeks after TMPD injection. Inflammatory monocytes are known to be recruited to inflamed tissue and contribute to tissue damage. These results suggest that inflammatory monocytes trafficking to the peritoneum might be important event leading to tissue damage in this model.