Sex-specific responses of monocytes to infectious challenges

• Applicant: Professorin Dr. Hannelore Lotter
• Subject Area: Immunology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 429191104

Innate immune cells, such as classical monocytes, are key players in infection control and early antigen recognition, which is a prerequisite for vaccination. Sex hormones modulate immune responses at the cellular level, and androgens are generally thought to play an immunosuppressive role. However, their influence on monocytes is unclear, with considerable evidence for their specific roles in immunity. In a murine model of hepatic amebiasis, a classical male-biased parasitic disease in humans and mice, liver damage occurs via an overwhelming recruitment and activation of classical inflammatory monocytes. This process is further enhanced by their production of chemokines such as CXCL1, which recruits other innate immune cells with immunopathological potential. We found that androgens increase the production of CXCL1 by monocytes of murine and human origin. However, the underlying androgen signaling pathways in monocytes are so far unknown. A more detailed understanding of the mode of action of androgens on monocytes could also help increase our understanding of their role in vaccination, to which women often show more vigorous responses. Antigen uptake and presentation by monocytes occurs through Fc gamma receptors (FcGR), particularly FcGRI. In both humans and mice, FcGRI expression on classical monocytes is significantly lower in males than in females, and this sex difference is even more pronounced upon stimulation. On the basis of these findings, we propose to characterize the signaling pathways activated by androgens in monocytes in vitro using a variety of specific blocking approaches, supported by transcriptome analyses of androgen-treated monocytes. We will furthermore study the specific role of androgens on monocytes in murine models of vaccination as well as in a human vaccine cohort. We hypothesize that androgens selectively regulate both activating and suppressing monocyte functions and that the identification of underlying critical molecular signaling pathways could be the basis for the development of future therapeutic approaches that would compensate for monocyte-related disadvantages in men in various diseases.

• DFG Programme: Research Units
• Subproject of: FOR 5068: Sex differences in immunity