Inflammatory monocyte-derived dendritic cells mediate autoimmunity in murine model of systemic lupus erythematosus

Abstract

Using a mouse model of systemic lupus erythematosus (SLE), we recently demonstrated that the two major manifestations of SLE are mechanistically independent because the type I IFN pathway leads to the autoantibody production whereas the NF-κB activation is sufficient for the development of glomerulonephritis. To further advance our understandings on the molecular pathways regulating the development of SLE, we studied the role of IRF8 because it controls both type I IFN and NF-κB pathways and saw that IRF8-deficient mice failed to develop either glomerulonephritis or the autoantibody production. Furthermore, these genetically engineered mice prompted us to realize the important role of Ly6C high inflammatory monocytes in the development of SLE. These monocytes migrate to the peritoneal cavity in WT and IRF7-deficient mice but not in IRF8-deficient mice, and there they produce both type I IFN and proinflammatory cytokines in WT mice, while in IRF7-deficient mice they only produce proinflammatory cytokines. Upon migration to the spleen, Ly6C high inflammatory monocytes differentiate into dendritic cells (DCs) which are capable of producing proinflammatory cytokines in response to dsDNA autoantigen. Collectively, type I IFN produced from inflammatory monocytes/monocyte-derived DCs might be essential for autoantibody production whereas proinflammatory cytokines produced from them might mediate tissue damages in this model. Our study reveals a specialized role for monocyte-derived antigen presenting cells in autoimmunity. Plasticity of monocyte might play an important role not only in the pathogenesis of the disease but also in flare-ups of the disease.

NLRP12 is an innate immune checkpoint for repressing IFN signatures and attenuating lupus nephritis progression

“…IFN-I production induced by pristane injection increases the expression levels of ISGs, such as Ccl2 and Cxcl-10 , to recruit myeloid cells, particularly inflammatory monocytes ( 28 ). In fact, the influx of monocytes plays a substantial role in the pathogenesis of LN ( 30 , 31 ), particularly their influx into the kidney, which is considered an indicator of GN ( 32 ). We observed that Nlrp12 –/– mice had greater levels of Ly6C hi monocyte infiltration in the glomerular basement membrane and mesangium ( Supplemental Figure 8A ).…”

Abnormal Changes of Monocyte Subsets in Patients With Sjögren’s Syndrome

“…Therefore, this study uncovered the abnormal changes in monocyte subsets and their transcriptomic changes in SjS patients, and identified TNFSF10 high/+ monocytes as a potential key player in SjS pathogenesis and a promising target for SjS treatment. Mononuclear phagocytes including monocytes are the main antigen presenting cells (APCs) and can initiate protective immune processes against pathogens, but they can also initiate autoimmune processes in autoimmune diseases (30)(31)(32). Recent studies have proven the existence of distinct monocyte subsets and they have critical roles in the development of some rheumatic diseases such as SLE and rheumatoid arthritis (RA), and targeting monocytes is a potential treatment for those diseases (17,33).…”

Pathogenesis of Paradoxical Reactions Associated with Targeted Biologic Agents for Inflammatory Skin Diseases

“…Studies in lupus-prone mice also demonstrated the importance of type I IFNs for SLE because NZB mice lacking the α-chain of the type I IFN receptor exhibited significantly decreased morbidity and mortality [ 34 ]. Furthermore, mice that were deficient in IFN regulatory factor 7, a master regulator of type I IFN-dependent immune responses, failed to produce autoantibodies when SLE was chemically induced [ 35 , 36 ]. Collectively, these findings underscore the role played by type I IFNs in the pathogenesis of SLE.…”