Sex and stress hormones control adrenal gland macrophage development and function"

Project Summary/Abstract: Chronic stress promotes a systemic inflammatory response that contributes to cardiovascular and metabolic disease (CVD), and even acutely augmented stress can exacerbate disease severity. In humans, consumption of high fat/high cholesterol diet (HFD) is a common co-factor driving chronic stress responses. Understanding mechanisms controlling the stress-response and its association with CVD diseases, which are nearly ubiquitous and a leading cause of mortality, will allow for development of impactful translational approaches to fight against this understudied disease. The AG is the primary source for steroid hormones, corticosterone and aldosterone that are produced in the cortex. Elevated corticosterone modifies glucose homeostasis, immunity, and tissue remodeling. Our prior work using a cold-temperature stress model showed that cold-stress drives the promotion of monocyte egress from bone marrow and exacerbated atherosclerosis. Therefore, we sought to determine whether the local immune cells in the AG were also responding to stress responses, either through cold-exposure or HFD feeding. Interestingly, we observed accumulation of lipid within AG resident macrophages sitting adjacent to hormone-producing endocrine cells in models of atherosclerosis, hypertension, or acute cold challenge. Tissue resident macrophages are typically tissue repair cells and lipid accumulation is associated with anti-inflammatory phenotypes in macrophages. AG macrophages have not been thoroughly described in literature, and their function in response to hormone signals is unknown. Through our preliminary studies of WT mice (chow-diet fed with no overt stressors), we identified two primary populations of macrophages present in the AG. These populations showed a sexual dimorphism in the representation of macrophage subsets when comparing adult male versus female mice. Furthermore, through single cell RNA- seq profiling between male and female AG immune populations, we identified gene programs associated with AG resident macrophages and found constitutive expression of the lipid-sensor Trem2, which was found to increased on AG macrophages following chronic challenge, supporting a role in responding to lipid-hormones. Loss of Trem2 was associated with lipid accumulation in the AG and elevated circulating corticosterone levels in the absence of challenge. Together, these observations led to the overarching hypothesis AG resident macrophage maintenance is controlled by sex hormone production, and that AG macrophages sense steroid hormones during stress responses to dampen inflammation and promote tissue health. Our extensive experience in studying tissue macrophage development and function, along with the utilization of new animal models make our group ideal to test these novel concepts. If true, the implications of this study will identify new approaches to regulate systemic inflammation responses through the modulation of AG associated macrophages, which might complement current lipid-control approaches used for high-risk CVD patients.