Sex differences in regulation of innate immune response by neurotransmitters - PROJECT SUMMARY Sex differences in immune responses underly variation in physiological processes and disease susceptibilities. However, there is limited insight into the sex-specific mechanisms that inform immune activation in the context of health and disease. Monocytes and polymorphonuclear neutrophils are the first line of defense against pathogenic insults and tissue damage, and also mediators of the homeostatic resolution process. Dysregulation of inflammatory vs immunosuppressive function of these myeloid cells is closely linked to disease pathogenesis. Our recent work identified metabolic and epigenetic signatures linked to the distinct function of monocytes and neutrophils in females versus males as well as sex differences in their response to the neurotransmitters γ- aminobutyric acid (GABA) and glutamate. Neurotransmitters are abundant chemical messengers with the potential to modulate immune cell activity. While neurotransmitter levels are altered in (patho)physiological states, their effects on innate immune response remain poorly defined. Building on these preliminary observations, we hypothesize that GABA and glutamate regulate monocyte and neutrophil activity in a sex- dependent manner through epigenetic, transcriptional, and metabolic programming. Here we will use mouse models, functional assays, and high-dimensional approaches to answer two central questions: (i) what the contributions of sex hormones versus chromosomes are in establishing myeloid cell programs and defining immunomodulatory effects of GABA/glutamate, and (ii) which transcriptomic, epigenetic, and metabolic mechanisms inform functional and sex-dependent GABA/glutamate response of monocytes and neutrophils. Unveiling the sex-specific roles of neurotransmitters and linked signaling pathways is important not only for improving the fundamental understanding of myeloid cell function but also for advancing therapeutic strategies by repurposing neurotransmitter modulators or targeting downstream signaling cascades in diseases characterized by innate immune dysregulation or exhibiting sex-bias. Upon successful completion of the proposal, we anticipate having identified (i) baseline sex differences in monocyte and neutrophil functionality, and the relative role of the sex steroids versus chromosomes in defining myeloid cell responses, and (iii) sex- specific transcriptional, metabolic, and epigenetic metaprograms that underlie the heterogenous monocyte and neutrophil activity. My lab is uniquely positioned to pursue this groundbreaking project and generate metadata that will drive future hypothesis-driven basic and translational research focused on the fine-tuning of myeloid cell activity through the modulation of neurotransmitter signaling.
