Androgens can modulate immunoregulation directly through gut cells and indirectly through alteration of microbiota composition/function in a lupus mouse model.

Abstract

Abstract Hormones and gut microbiota affect lupus. In female NZBxNZW1(BWF1) mice, androgen treatment abrogates lupus; castration/treatment with androgen receptor blocker (flutamide) induces disease in BWF1 male mice. Gut microbiota alterations have been reported in lupus. Our goal is to understand the androgen/gut microbiota relationship, and its affect on lupus. We found male castration decreases peripheral, not thymic, derived Tregs; this correlates with decreased gut CD103 dendritic cells (CD103DC) function (induce Treg conversion) and RALDH2 [required for retinoic acid (RA) production) expression. CD103DC have very low androgen receptor (AR) expression, thus unlikely to be affected by androgens. We found that lamina propria stromal cells (LPSC), a major source of RA (via RALDH1/2 expression) required for normal gut CD103DC development, express very high AR levels. Castration/flutamide treatment in male mice decreased RALDH1/2 expression in LPSC, suggesting androgens may affect CD103DC function through LPSC. Castration/flutamide treatment also altered gut microbiota composition. Interestingly, intact male microbiota transfer to castrated male mice restored RALDH2 expression and CD103DC function, suggesting male microbiota factors may also alter CD103DC function. Metabolomic analysis of castrated male feces showed reduced phytanic acid (PA) levels. Administration of PA in vitro/in vivo restored castrated CD103DC function. These data strongly suggest that androgens alter (1) immunoregulatory function through gut cells and (2) gut microbiota composition/function that in turn modulate immunoregulatory function, and reveal how androgens may influence lupus and provide the basis for effective therapy development. Funded by a TIL grant from the Alliance for Lupus Research and the NIH (R01AR067188)