Sexual dimorphism in sepsis susceptibility: Effects of reproductive hormones on microbial pattern recognition receptor expression

Sex-based differences in innate immune responses to bacterial infection are evident in human patients and animal models of disease. Females are less susceptible to the development of bacterial infections and subsequent bacteremia and/or sepsis while males exhibit a greater incidence of such infections and are more likely to develop fatal sequelae. While the precise effects and mechanisms of action remain to be determined, it is apparent that male and female reproductive hormones can have direct effects on the expression and function of key bacterial pattern recognition receptors on innate immune cells. Changes in the expression of these receptors are likely to have profound effects on the production of the inflammatory mediators responsible for the lethal nature of septic shock and may underlie the observed sexual dimorphism demonstrated in immune responses to bacterial endotoxins. In the present studies, we have determined the role of testosterone and estradiol on TLR4 expression from murine macrophages. Testosterone suppresses both total and cell-surface TLR4 expression from macrophages, both in vitro and in vivo, and decreases inflammatory mediator production following LPS challenge. Estradiol, however, exhibits much more complicated effects on pattern recognition receptor expression. Long-term exogenous estradiol treatment in vivo augments cell-surface but not total TLR4 expression, with a corresponding increase in inflammatory mediator production following LPS challenge. However, acute treatment of macrophages with estradiol results in an opposite effect with decreased levels of cell-surface TLR4 expression and inflammatory mediator production, and this effect was found to be mediated by the novel estrogen receptor GPR30. As such, estrogens may be able to reduce the devastating inflammation associated with acute overactive host responses such as septic shock without compromising long-term defense against infectious organisms.