Androgens Promote an il10/tgfb-expressing Neutrophil Immunomodulatory Phenotype.

M. V. SCALERANDI; C. LEIMGRUBER ; J. P. NICOLA; N. PEINETTI; C. R. MARIANA; O. SOEHNLEIN; G. B. MENEZES; C. MALDONADO; A. QUINTAR

Congreso; 47th Annual Meeting of the German Society for Immunology.; 2017

German Society for Immunology (DGfI)

Sexual hormones influence the immune response, with androgens exerting a suppressive effect on adaptiveimmunity. Males appear more susceptible to bacterial infection than females but there is scarce evidenceabout the role of androgens on the innate immune/inflammatory response. Therefore, we addressed the roleof testosterone modulating neutrophil recruitment, activity, and phenotype during the inflammatory responsein the prostate gland. Adult male Wistar rats were orchiectomized and immediately replaced with testosteroneat physiological level (T) or vehicle (OX), and then subjected to an intra-prostatic inoculation of E. coli (5 days,T+BP and OX+BP groups) or LPS (24 hs, T+LPS and OX+LPS groups). T+BP animals showed a higher neutrophilinfiltration compared to OX+BP, with intense E. coli immunostaining, correlating with the presence ofphagocytosed bacteria in active neutrophils by electron microscopy. In LPS-induced prostatitis, testosteronetreatment also promoted a higher neutrophil recruitment (Gr+ cells/gland assessed by flow cytometry, whichwere correlated with an increased mRNA expression of cxcl1 and cxcl2), with these cells having a lowermyeloperoxidase (MPO) activity. Sorted Gr+ infiltrating neutrophils showed a higher il10/tgfb/il6- and loweril12-mRNA expression in T+LPS by qPCR. In order to determine whether testosterone is able to modulateneutrophils in androgen-independent sites, intravital microscopy was used for analyzing the recruitment to theliver in LPS-injected (ip. for 6h) mice treated with T (T+LPS) or the anti-androgen flutamide (FL+LPS). T+LPSexhibited a higher number of neutrophils in the liver sinosoids. Testosterone also increased LPS-induced Gr+cell recruitment to the peritoneum in rats compared to castrated animals. Those testosterone-promotedperitoneal cells displayed a lower MPO activity and a reduced bactericidal ability (when coincubating ex vivowith E. coli). Finally, these neuthophils showed a higher cxcl1, cxcl2, il10 and, tgfβ mRNA but reduced il1b, il12,and tnfα mRNA expression. These findings reveal an intriguing role for testosterone on the early inflammatoryresponse, with neutrophils being a main target. Testosterone increases local chemokine expression, leading toa higher recruitment of neutrophils to the site of infection. However, testosterone favors anil10hightgfbhighil12lowMPOlow phenotype, with reduced efficiency in killing bacteria.