Sexual Dimorphism in Innate Immunity: The Role of Sex Hormones and Epigenetics

Abstract

Sexual dimorphism refers to differences between biological sexes that extend beyond sexual characteristics. In humans, sexual dimorphism in the immune response has been well demonstrated, with females exhibiting lower infection rates than males for a variety of bacterial, viral, and parasitic pathogens. There is also a substantially increased incidence of autoimmune disease in females compared to males. Together, these trends indicate that females have a heightened immune reactogenicity to both self and non-self-molecular patterns. However, the molecular mechanisms driving the sexually dimorphic immune response are not fully understood. The female sex hormones estrogen and progesterone, as well as the male androgens, such as testosterone, elicit direct effects on the function and inflammatory capacity of immune cells. Several studies have identified a sex-specific transcriptome and methylome, independent of the well-described phenomenon of X-chromosome inactivation, suggesting that sexual dimorphism also occurs at the epigenetic level. Moreover, distinct alterations to the transcriptome and epigenetic landscape occur in synchrony with periods of hormonal change, such as puberty, pregnancy, menopause, and exogenous hormone therapy. These changes are also mirrored by changes in immune cell function. This review will outline the evidence for sex hormones and pregnancy-associated hormones as drivers of epigenetic change, and how this may contribute to the sexual dimorphism. Determining the effects of sex hormones on innate immune function is important for understanding sexually dimorphic autoimmune diseases, sex-specific responses to pathogens and vaccines, and how innate immunity is altered during periods of hormonal change (endogenous or exogenous).

Keywords: cross-sex hormone treatment; epigenetics; innate immunity; pregnancy hormones; progesterone and estradiol; sexual dimorphism.

Figure 1

Steroid hormone signaling. Ligand-bound nuclear hormone receptors bind to hormone response elements (HREs) in the promoters of target genes (genomic signaling). Coactivators, corepressors, and epigenetic regulatory enzymes interact with ligand-bound nuclear hormone receptors, regulating their effect on transcription. The activation or repression of target genes (potentially orchestrated by epigenetic changes) can alter the cellular response in a hormone-dependent manner. Signaling of steroid hormones can occur rapidly via membrane hormone receptor signaling (non-genomic signaling), resulting in activation of PI3K/Akt/MAPK pathways and downstream TF signaling pathways.

Figure 2

Hormone fluctuations in human females during aging and pregnancy. These hormone fluctuations are associated with immune function and susceptibility to certain inflammatory diseases. Several studies have performed epigenetic and transcriptional profiling at different stages of life: i) (122), ii) (123), iii) (124), iv) (125), v) (126), vi) (127), vii) (128), and viii) (129).

Figure 3

Summary of selected pregnancy-associated and sex hormone effects on innate immune cells. Findings in four cell types, Mo, monocytes/macrophages; Neu, Neutrophils; DC, Dendritic cells; NK, Natural Killer cells; are shown. Shapes correspond to hormone: yellow circle—hCG, pink rectangle—estrogen, orange chevron—progesterone, blue triangle—testosterone, and arrows indicate if the hormone attenuated or increased a response/phenotype.