Abstract
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.
Highlights
Neutrophil granulocytes lead the initial leukocyte influx to sites of injury in order to eliminate invading pathogens or damaged tissues
Various studies have uncovered important immune regulatory functions for androgens, including effects on neutrophil accumulation [31,32,33], maturation, activation [34], and survival [35]. In line with this evidence, we here report that testosterone increases local chemokine expression, leading to a higher recruitment of neutrophils to the site of infection, but at the same time, these cells exhibit a “N2-like” phenotype with a reduced efficiency in killing bacteria and high expression of immunomodulatory molecules such as IL10 and TGFβ1
We observed that the presence of testosterone leads to an increased bacterial-induced mRNA expression of CXCL1 and CXCL2, which was associated to a higher neutrophil recruitment
Summary
Neutrophil granulocytes lead the initial leukocyte influx to sites of injury in order to eliminate invading pathogens or damaged tissues Their response is mediated by phagocytosis and NETosis, as well as by releasing defensins, enzymes, and cytokines to active the immune response [1]. If the inflammatory process is not controlled, the products generated by neutrophils can induce multiple tissue alterations and loss of cellular function [3, 4] This is important in endotoxemia- and burn-induced multiple organ dysfunction and in unresolved infections of the reproductive tract, where neutrophil activation could be harmful causing degradation of the extracellular matrix and additional gamete damage beyond that associated with the initial injury [5,6,7]. Little is known about different neutrophil phenotypes promoted by non-tumoral environments as metabolic or hormonal imbalance
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