The Influence of Ontogeny and Physiological Microbial Exposure on Macrophage Maintenance and Function

Macrophages are highly phagocytic cells found in almost every tissue of the body and are involved in several physiological processes, including pathogen defense and tissue development. The work presented in this thesis sought to determine whether factors such as ontogeny and microbial diversity can affect macrophage maintenance and function in homeostatic conditions and disease. First, we isolated and characterized a unique population of macrophages that exists in the vasculature during steady state. Using lineage-tracing techniques we demonstrated that adult vascular macrophages derive from embryonic and adult origins. We found that survival and maintenance of this population is dependent on the interaction between the fractalkine receptor and its ligand. This study highlights the importance of tracking the ontogenetic source of macrophages in tissues as we see key differences in maintenance and function between resident and recruited subsets in the vasculature. The second chapter in this dissertation focuses on evaluating whether exposure to diverse environmental pathogens can affect macrophage maintenance and function. It was observed that physiological exposure to microbes significantly alters monocyte and macrophage subsets in mice – specifically, we detected an expansion of resident macrophages in the peritoneum; we note that local proliferation, and not monocyte recruitment, accounts for this change. Microbial exposure did not affect phagocytosis, responses to bacterial pathogens and sepsis, and only slightly altered cytokine production in response to toll-like receptors (TLRs) agonists. In a mouse model of atherosclerosis, we found that microbial exposure reduces lesion development exclusively at 8 weeks. In summary, this work examined the influence of ontogeny and microbial exposure on macrophage function in the steady state and in the course of disease.Ph.D