S100a9-deficiency accelerates lupus disease and renal failure in male (NZB x NZW)F1 mice

Abstract

All (NZB x NZW)F1 (BWF1) female mice develop lupus-like disease, compared to ~30% of male BWF1 mice. Our previous research described an immunosuppressive effect of Gr1hiCD11bhi cells in male BWF1 mice. Specifically, as BWF1 mice age, female Gr1hi cells lost their ability to suppress altogether, while antibody-mediated depletion of Gr1hi cells accelerated disease development in male mice only. Reverse transcriptase-PCR studies revealed upregulated S100a9 and S100a8 mRNA levels in male flow-sorted Gr1hi cells as compared to cells from female BWF1 mice and non-autoimmune stains, leading us to hypothesize that S100a8/a9 produced by male Gr1hi cells is immunosuppressive. To study this, we created S100a9-deficient BWF1 mice. Our results showed spleen weight and splenocyte count, indicators of lupus advancement, were significantly higher in S100a9−/−male mice. Additionally, increased IgG-IC deposition in kidney glomeruli of S100a9−/−male mice was observed along with a significant increase in serum anti-chromatin IgG levels. Deficiency of S100a9 also resulted in increased frequencies of memory B cells and plasma cells in male mice, but not in female mice. Interestingly, S100a9-deficiency caused an accumulation of Gr1hiCD11b+ splenocytes in male mice. We speculated that this is due to a lack of trafficking of Gr1hi cells into the glomerulus of the kidney due to S100a9-deficiency. Subsequent IHC confirmed the lack of S100a9 expression in kidneys from S100a9-deficient mice. Finally, H/E and Trichrome stainings indicated accelerated renal failure in S100a9−/−mice. In conclusion, S100a9 may function as a chemoattractant of Gr1hi cells exerting immunosuppression and protection against lupus-like renal disease in male BWF1 mice.