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

LEIMGRUBER, C; CUELLO RUBIO, MM; MALDONADO, CA; NICOLA, JP; SOEHNLEIN, O; SCALERANDI, MV; QUINTAR, AA; PEINETTI, N; MENEZES, GB

Erlangen

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 adaptive immunity. Males appear more susceptible to bacterial infection than females but there is scarce evidence about the role of androgens on the innate immune/inflammatory response. Therefore, we addressed the role of testosterone modulating neutrophil recruitment, activity, and phenotype during the inflammatory response in the prostate gland. Adult male Wistar rats were orchiectomized and immediately replaced with testosterone at 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 neutrophil infiltration compared to OX+BP, with intense E. coli immunostaining, correlating with the presence of phagocytosed bacteria in active neutrophils by electron microscopy. In LPS-induced prostatitis, testosterone treatment also promoted a higher neutrophil recruitment (Gr+ cells/gland assessed by flow cytometry, which were correlated with an increased mRNA expression of cxcl1 and cxcl2), with these cells having a lower myeloperoxidase (MPO) activity. Sorted Gr+ infiltrating neutrophils showed a higher il10/tgfb/il6- and lower il12-mRNA expression in T+LPS by qPCR. In order to determine whether testosterone is able to modulate neutrophils in androgen-independent sites, intravital microscopy was used for analyzing the recruitment to the liver in LPS-injected (ip. for 6h) mice treated with T (T+LPS) or the anti-androgen flutamide (FL+LPS). T+LPS exhibited 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-promoted peritoneal cells displayed a lower MPO activity and a reduced bactericidal ability (when coincubating ex vivo with 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 inflammatory response, with neutrophils being a main target. Testosterone increases local chemokine expression, leading to a higher recruitment of neutrophils to the site of infection. However, testosterone favors an il10(high)tgfb(high)il12(low)MPO(low) phenotype, with reduced efficiency in killing bacteria.