Self-renewal and phenotypic conversion are the main physiological responses of macrophages to the endogenous estrogen surge.
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 E2and 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 E2and, 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, E2promoted 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.
Center of Excellence on Neurodegenerative Diseases and Department of Pharmacological and Biomolecular Sciences, University of Milan, Italy.
Giovanna
G
Pepe
Department of Health Sciences, University of Milan, Italy.|Fondazione Filarete, Milan, Italy.
Daniele
D
Braga
Department of Medical Biotechnologies and Translational Medicine, University of Milan, Italy.|Humanitas Clinical and Research Center, Rozzano, Italy.
Tiziana A
TA
Renzi
Center of Excellence on Neurodegenerative Diseases and Department of Pharmacological and Biomolecular Sciences, University of Milan, Italy.
Alessandro
A
Villa
Department of Pharmaceutical Sciences, University of Padua, Italy.
Chiara
C
Bolego
Department of Health Sciences, University of Milan, Italy.|Fondazione Filarete, Milan, Italy.
Francesca
F
D'Avila
Department of Health Sciences, University of Milan, Italy.|Fondazione Filarete, Milan, Italy.
Cristina
C
Barlassina
Center of Excellence on Neurodegenerative Diseases and Department of Pharmacological and Biomolecular Sciences, University of Milan, Italy.
Adriana
A
Maggi
Department of Medical Biotechnologies and Translational Medicine, University of Milan, Italy.|Humanitas Clinical and Research Center, Rozzano, Italy.
Massimo
M
Locati
Center of Excellence on Neurodegenerative Diseases and Department of Pharmacological and Biomolecular Sciences, University of Milan, Italy.
Elisabetta
E
Vegeto
D000075803:Angiopoietin-Like Protein 4 / Q000235:genetics / Q000276:immunology; D000818:Animals; D001119:Arginase / Q000235:genetics / Q000276:immunology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D007113:Immunity, Innate; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D008262:Macrophage Activation / Q000187:drug effects*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010052:Ovariectomy; D010538:Peritonitis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D010641:Phenotype; D059467:Transcriptome; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000276:immunology; D015054:Zymosan
D000075803:Angiopoietin-Like Protein 4; C407088:Angptl4 protein, mouse; D018797:Cell Cycle Proteins; C556062:IL10 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D016753:Interleukin-10; D004958:Estradiol; D015054:Zymosan; C544448:Arg1 protein, mouse; D001119:Arginase