THE PHYSIOLOGICAL RESPONSE OF RESIDENT MACROPHAGES TO THE ESTROGEN SURGE

Macrophages are resident immune cells that play a key role in host defense against pathogenic infections and in inflammatory responses and in physiological tissue remodelling. They are able to respond to a variety of microenvironmental stimuli, adopting different activation states depending on the activating signal and context, in order to eliminate the pathogen and restore homeostasis.
Humans show strong sex differences in immunity to infection and autoimmunity, suggesting that sex hormones modulate immune responses. Indeed, estrogens regulate cells and pathways of the innate and adaptive immune systems, as well as immune cell development. Previous studies showed that 17β-estradiol (E2) is able to modulate the reactivity of macrophages during inflammation, down-regulating the expression of inflammatory genes. However, a full comprehension of the molecular details by which estrogens modulate macrophage activity is still unclear. To fill this gap we performed a transcriptomic analysis followed by biological assays of peritoneal macrophages isolated from female mice both with different endogenous estrogen levels and following short and long term estrogen administrations.
The bioinformatic data suggested that E2 modulates important biological processes in macrophage physiology; among these, proliferation and the induction of an anti-inflammatory and pro-resolution phenotype emerged as mostly significant. We thus confirmed this evidence by proving, through gene expression, FACS analyses and BrdU incorporation studies, that the proliferative index and macrophage cell number are induced by the estrogen surge. Furthermore, we demonstrated that hormone administration induces a dynamic activation process that evolves towards a pro-resolving phenotype through the synthesis of IL10. Moreover, we observed that this activity is also maintained during peritoneal inflammation.
By investigating the effects of E2 on microglia, a different macrophage population, my data highlighted the diversity in the E2 response of macrophages that reside in different tissues and the influence of the microenvironment on the hormone responsiveness and provided a list of E2 target genes that can be used as biomarkers for pharmacological and translational studies.
Altogether, these results deepen our understanding of the endocrine-immune interactions and allow future studies on their relevance for the pathogenesis and development of therapeutic strategies of inflammatory pathological conditions.