Self-renewal and phenotypic conversion are the main physiological responses of macrophages to the endogenous estrogen surge

Abstract

Beyond the physiology of reproduction, estrogen controls the homeostasis of several tissues. Although macrophages play a key role in tissue remodeling, the interplay with estrogen is still ill defined. Using a transcriptomic approach we first obtained a comprehensive list of genes that are differentially expressed in peritoneal macrophages in response to physiological levels of 17β-estradiol (E2) injected in intact female mice. Our data also showed the dynamic nature of the macrophage response to E2 and pointed to specific biological programs induced by the hormone, with cell proliferation, immune response and wound healing being the most prominent functional categories. Indeed, the exogenous administration of E2 and, more importantly, the endogenous hormonal surge proved to support macrophage proliferation in vivo, as shown by cell cycle gene expression, BrdU incorporation and cell number. Furthermore, E2 promoted an anti-inflammatory and pro-resolving macrophage phenotype, which converged on the induction of genes related to macrophage alternative activation and on IL-10 expression in vivo. Hormone action was maintained in an experimental model of peritoneal inflammation based on zymosan injection. These findings highlight a direct effect of estrogen on macrophage expansion and phenotypic adaptation in homeostatic conditions and suggest a role for this interplay in inflammatory pathologies.

The estrogen–macrophage interplay in the homeostasis of the female reproductive tract

“…Tissue macrophages also derive from hematopoiesis, as blood monocytes may infiltrate into tissues and differentiate into mature cells (Schulz et al, 2012;Sieweke and Allen, 2013;Yona et al, 2013). Self-F o r P e e r R e v i e w renewal of tissue resident macrophages is regulated by the lineage specific growth factor, macrophagecolony stimulating factor (CSF1), as well as by immune and endocrine signals, such as interleukin-4 (IL-4), IL-33 and estrogens, in a tissue-specific manner (Hashimoto et al, 2013;Jackson-Jones et al, 2016;Jenkins et al, 2013;Pepe, Braga, et al, 2017;Pepe, De Maglie, et al, 2017;Tagliani et al, 2011). Multiple physiological signals, including CSF1 and the chemokines Monocyte Chemoattractant Protein-1 (MCP-1/CCL2) and Macrophage Inhibitory Protein 1-α (MIP-1α/CCL3), are clearly involved in the recruitment of monocytes (Pollard et al, 1987(Pollard et al, , 1998Robertson et al, 1996;Wood et al, 1997;Long et al, 1998;Klotz et al, 2002;Moldenhauer et al, 2010;Wheeler et al, 2018).…”

“…Beyond immunity, recent investigations demonstrated novel functions for macrophages, which are dictated by a vast array of physiological cues and in response to specific regulatory interactions that macrophages establish with the specific cell types and matrix components within tissues (Gordon and Plüddemann, 2017). Indeed, macrophages were proved to act in diverse organs of the female reproductive tract (FRT) by non-immune processes and recently shown to undergo a specific phenotypic adaptation in response to estrogens and estrogens-regulated mediators that promotes immune tolerance and tissue remodeling (Pollard et al, 1998;Pepe, Braga, et al, 2017). These novel data encourage a revision of the molecular and biological details of the macrophage response to estrogens and the evidence on the distribution and activity of these cells in the FRT, with insight into the relevance of this endocrineimmune interplay in FRT homeostasis and diseases.…”

Origin and microenvironment contribute to the sexually dimorphic phenotype and function of peritoneal macrophages

“…It is therefore essential to understand how intrinsic factors such as sex control the behaviour of innate immune effector cells. Specifically, sex has been proposed to affect macrophage behaviour, such as influencing the differentiation of brain microglia 32–34 and sex hormones appear able to directly regulate gene expression 35 and proliferation 36 of macrophages. While previous studies have considered the effects of sex on peritoneal macrophage behaviour, many of these have focussed on in vitro functional assessments using macrophages elicited by injection of an irritant or inflammatory agent 37 , or have not appreciated the complexity of the peritoneal macrophage compartment 36, 38 .…”

Maternal tamoxifen treatment expands the macrophage population of early mouse embryos

“…A second assumption in the use of tamoxifen-inducible reporters is that the drug does not alter the differentiation of monocyte-macrophage cells in the embryo, based in part upon the reported lack of expression of the estrogen receptors in foetal haematopoietic progenitors (14). However, this assumption is questioned by evidence of the direct effects of estrogen on macrophage gene expression and self-renewal in vivo and in vitro (15). Patel et al (13) noted that >40% of published studies that use tamoxifen to generate conditional mutations lack controls for the impact of tamoxifen.…”