Deciphering hormonal regulation of neutrophil biology

Project Summary/Abstract
Although aging is a conserved phenomenon across evolutionary distant species, key aspects of biological
process have been found to differ between males and females of the same species during aging. For instance,
accumulating evidence suggests that immune cells of male vs. female individuals are clearly distinct
throughout life. Despite these clear differences and their potential significance, biomedical research has
historically focused exclusively on male individuals. Thus, sex- driven differences, their molecular
underpinning and impact on various aspects of adult health, including lifelong immune responses, are still
poorly understood. Interestingly, both sex hormones (i.e. androgens vs. estrogens) and sex-chromosomes
(i.e. XX vs. XY) have key impact outside of reproduction and gonadal development. Indeed, accumulating
evidence supports the notion of widespread sex-dimorphism in biological processes. For example, immune
responses differ between biological sexes, with a more robust immune response in females vs. increased
susceptibility to infection in males. Neutrophils are a major leukocyte population serving as a “first line of
defense” against infections. We have observed strong sex-dimorphism in the transcriptome, metabolome and
lipidome of murine neutrophils, as well as changes in neutrophil-mediated immune phenotypes. Together, our
results suggest that mechanisms involving gonadal hormones and/or sex chromosomes can regulate
neutrophil-based immunity. We hypothesize that mechanisms involving both sex chromosomes and
lifelong exposure to gonadal hormones independently modulate neutrophil-based genomic networks
and immune phenotypes throughout life. To test our hypothesis, we will investigate how neutrophil-based
phenotypes are fine-tuned as a function of sex throughout life. Sex hormones and sex chromosome
complement are intimately linked in wild-type animals, complicating the study of determinants of sex-dimorphic
phenotypes. To address this shortcoming, we will leverage an innovative model of adult somatic-sex
reprogramming (the adult Foxl2-iKO) to assess the impact of hormonal vs. genetic sex on neutrophil
phenotypes throughout life. This unique and tractable system will enable us to understand the consequences
of adult exposures to higher levels of estrogens vs. androgens on immune responses. Together, our proposed
experiments will provide insights on sex-dimorphic mechanisms of immune regulation and reveal how
hormonal inputs may exert lifelong impact on immune cells.

Grant Number: 5R01AG076433-04
NIH Institute/Center: NIH
Principal Investigator: Berenice Benayoun