Macrophages (M) are among the immune system's most important defenders of the body by protecting against infection and injury but they also accelerate numerous diseases. Recent studies indicate that many tissue M are generated during embryonic development and maintain themselves in adults in the steady-state. In diseased tissues, however, many M originate from circulating monocytes (Mo). For example, we found that circulating Mo often in?ltrate the ischemic myocardium, atherosclerotic plaques and growing tumors, where they differentiate into M and can promote disease. These circulating Mo can be released in large quantities from different reservoir locations, including th bone marrow and spleen, and various diseases enhance Mo production in these reservoirs by amplifying hematopoietic stem and progenitor cells (HSPC) locally. At present, an accurate understanding of disease-induced M responses is lacking and requires a more comprehensive analysis of the origins and dynamics of these cells at the organismal level. The research proposed in this application will de?ne both the quantity and quality of tissue M based on thei origins. We propose that, in disease, distinct anatomical sites produce different types of M precursors and we will thus test the hypothesis that disease-associated tissue M responses can be tailored by manipulating these cells' topo-ontogenic sources. First, by taking the entire HSPC?Mo?M lineage into account we will identify the most important kinetic processes that de?ne the quantity of disease-associated M (aim 1). Second, by considering the different origins of these M we will uncover maturational pathways that in?uence their quality in vivo (aim 2). Our ?ndings have therapeutic potential because in both aims we will de?ne how Ang II pathway manipulations control M. Ang II is a newly identi?ed driver of HSPC/Mo/M-mediated in?ammation that is active in a variety of diseases (cancer, atherosclerosis, myocardial infarction) and can be targeted with FDA-approved drugs. Our goal is to develop new advances that can be used to restrain unwanted in?ammatory reactions or instead promote delivery of protective immunity to tissue. Our experiments will use the so-called KP tumor mouse model because we have generated data indicating that: i) M in KP tumors have a dominant phenotype and promote disease; ii) many of these M originate from HSPC and Mo that are produced in bone marrow and spleen; iii) HSPC?Mo?M lineage ampli?cation in KP mice resembles the one observed in other disease models including myocardial infarction and atherosclerosis; and iv) the hormone Angiotensin (Ang) II ampli?es disease-promoting M in KP mice. Also, we have assembled a team of experts in imaging, leukocyte traf?cking, data modeling and integrative biology to accomplish our goals.
This research will define both the quantity and quality of tissue macrophages based on their topo-ontogenic sources. We propose that distinct anatomical sites and inflammatory conditions influence the quantity and quality of macrophage precursors and we will thus test the hypothesis that tissue macrophage responses can be tailored by manipulating the cells' topo-ontogenic sources.
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