Neutrophils are major effectors of acute inflammation against infection and tissue damage, with ability to adapt their phenotype according to the microenvironment. Although sex hormones regulate adaptive immune cells, which explains sex differences in immunity and infection, little information is available about the effects of androgens on neutrophils. We therefore aimed to examine neutrophil recruitment and plasticity in androgen–dependent and –independent sites under androgen manipulation. By using a bacterial model of prostate inflammation, we showed that neutrophil recruitment was higher in testosterone-treated rats, with neutrophil accumulation being positively correlated to serum levels of testosterone and associated to stronger inflammatory signs and tissue damage. Testosterone also promoted LPS-induced neutrophil recruitment to the prostate, peritoneum, and liver sinusoids, as revealed by histopathology, flow cytometry, and intravital microscopy. Strikingly, neutrophils in presence of testosterone exhibited an impaired bactericidal ability and a reduced myeloperoxidase activity. This inefficient cellular profile was accompanied by high expression of the anti-inflammatory cytokines IL10 and TGFβ1, which is compatible with the “N2-like” neutrophil phenotype previously reported in the tumor microenvironment. These data reveal an intriguing role for testosterone promoting inefficient, anti-inflammatory neutrophils that prolong bacterial inflammation, generating a pathogenic environment for several conditions. However, these immunomodulatory properties might be beneficially exploited in autoimmune and other non-bacterial diseases.

Androgen signaling in prostate smooth muscle cells (pSMCs) is critical for the maintenance of prostate homeostasis, the alterations of which are a central aspect in the development of pathological conditions. Testosterone can act through the classic androgen receptor (AR) in the cytoplasm, eliciting genomic signaling, or through different types of receptors located at the plasma membrane for nongenomic signaling. We aimed to find evidence of nongenomic testosterone-signaling mechanisms in pSMCs and their participation in cell proliferation, differentiation, and the modulation of the response to lipopolysaccharide. We demonstrated that pSMCs can respond to testosterone by a rapid activation of ERK1/2 and Akt. Furthermore, a pool of ARs localized at the cell surface of pSMCs is responsible for a nongenomic testosterone-induced increase in cell proliferation. Through membrane receptor stimulation, testosterone favors a muscle phenotype, indicated by an increase in smooth muscle markers. We also showed that the anti-inflammatory effects of testosterone, capable of attenuating lipopolysaccharide-induced proinflammatory actions, are promoted only by receptors located inside the cell. We postulate that testosterone might perform prohomeostatic effects through intracellular-initiated mechanisms by modulating cell proliferation and inflammation, whereas some pathological, hyperproliferative actions would be induced by membrane-initiated nongenomic signaling in pSMCs.

Candida albicans is the prevalent etiological agent in acute vulvovaginal infection and the most severe chronic condition known as recurrent vulvovaginal candidiasis (VVC). A critical role of local innate immunity in defense and pathogenesis of vaginal infection by Candida is proposed. The fungal recognition by the innate immune receptor is an essential step for the induction of local responses including cytokines and antimicrobial peptides (AMPs) production for host protection. Using TLR2-deficient mice, we characterized the early innate immune response during VVC. Intravaginal challenge of TLR2-/- mice with C. albicans demonstrated that in response to the initial massive penetration, a strong local inflammatory reaction with recruitment of polymorphonuclear neutrophils was developed. Both interleukin 1β (IL1β)-regarded as the hallmark of VVC immunopathogenesis-and IL6 were increased in vaginal lavage. Murine beta defensin 1 (mBD1), a constitutive AMP with fungicidal and chemotactic activity, was significantly upregulated in wild type (WT) animals in response to infection. Interestingly, in the absence of TLR2 recognition, levels of mBD1 RNA more than twice higher than those in WT infected animals were observed. Interestingly, our results demonstrate that TLR2 signaling is important to control the fungal burden in the vaginal tract. These finding provide new evidence about the role of this innate receptor during VVC.

Prostatic smooth muscle cells (pSMCs) differentiation is a key factor for prostatic homeostasis, with androgens exerting multiple effects on these cells. Here, we demonstrated that the myodifferentiator complex Srf/Myocd is up-regulated by testosterone in a dose-dependent manner in primary cultures of rat pSMCs, which was associated to the increase in Acta2, Cnn1, and Lmod1 expressions. Blocking Srf or Myocd by siRNAs inhibited the myodifferentiator effect of testosterone. While LPS led to a dedifferentiated phenotype in pSMCs, characterized by down-regulation of Srf/Myocd and smooth muscle cell (SMC)-restricted genes, endotoxin treatment on Myocd-overexpressing cells did not result in phenotypic alterations. Testosterone at a physiological dose was able to restore the muscular phenotype by normalizing Srf/Myocd expression in inflammation-induced dedifferentiated pSMCs. Moreover, the androgen reestablished the proliferation rate and IL-6 secretion increased by LPS. These results provide novel evidence regarding the myodifferentiating role of testosterone on SMCs by modulating Srf/Myocd. Thus, androgens preserve prostatic SMC phenotype, which is essential to maintain the normal structure and function of the prostate. J. Cell. Physiol. 232: 2806-2817, 2017. © 2016 Wiley Periodicals, Inc.

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Androgen deprivation therapy (ADT) is the longstanding treatment for advanced prostate cancer (PC) because androgen receptor (AR) is the key therapeutic vulnerability for this disease. Bipolar androgen therapy (BAT) — the rapid cycling of supraphysiologic androgen (SPA) and low serum testosterone levels — is an alternative concept, but not all patients respond and acquired resistance can occur. In this issue of the JCI , Sena et al. developed a gene signature indicative of high AR activity to predict patient response to BAT, including a decline in both serum prostate-specific antigen (PSA) and tumor volume. Preclinical models showed that AR-mediated suppression of MYC, known to drive PC, was associated with decreased cell growth following SPA treatment. Because BAT eventually leads to resistance, the authors tested cycling between SPA and AR antagonism in a patient-derived xenograft and observed a delay in tumor growth. These findings represent a major step toward the informed use of BAT for advanced PC.