Calcium binding protein S100a9 protects male lupus-prone BWF1 mice from disease development (IRC4P.448)

Abstract

Abstract Testosterone protects from SLE pathogenesis, yet the mechanism of protection remains unknown. Using the (NZB x NZW)F1 (BWF1) mouse model of SLE, we have previously shown that immunosuppressive Gr1+CD11b+ cells are elevated in protected male BWF1 mice compared with females. Female and male Gr1+ cells use different mechanisms of suppression: reactive oxygen and nitrogen species (ROS/NOS) (female), or a secreted component independent of ROS/NOS production (male). Furthermore, female Gr1+ cells lose their capacity to suppress as the mice age. In support hereof, in vivo depletion of Gr1+ cells accelerated disease development in male mice only. Calcium-binding protein S100a9 is induced by inflammation and has been shown to exert either proinflammatory or immunosuppressive functions. Finding that male-derived Gr1+ cells express 3-4 fold higher levels of S100a9 mRNA than females, we hypothesized that S100a9 is the immunosuppressive mechanism used by male Gr1+ cells. Using S100a9-/- BWF1 mice we show that male-derived Gr1+ cells indeed use S100a9 to suppress plasma cell differentiation in vitro. Moreover, BWF1.S100a9-/- males developed increased serum ANA levels and IgG-IC deposition in the kidney glomeruli, and accelerated renal failure, while only the kidney phenotype was somewhat affected in BWF1.S100a9-/- female mice. In conclusion, differential regulation of S100a9 by male and female Gr1+ cells may contribute to the differential development of lupus in male and female BWF1 mice.