Differentiation and Function of Monocytes and Macrophages

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Resident MΦs naturally reside freely floating in peritoneal fluid. To counteract the problem that phagocytosis of cargo is inefficient in fluid, peritoneal MΦs produce Factor V to raise its local levels and facilitate formation of interstitial clots upon induction of inflammation. The clots in turn bring MΦs and microbes out of the fluid phase and into a 3-D environment together. This clotting reaction operates with induced MΦ adhesion onto mesothelial membranes to collectively account for the classical "MΦ disappearance reaction" (MDR). MDR in the peritoneum may also require inflammasome activation, which may then lead to cell death that accounts for an extended period of MΦ disappearance. Indeed, when the stimulus inciting the MDR is robust, Factor V+ resident MΦs disappear for several weeks, likely leaving the peritoneal cavity susceptible to future infectious and noninfectious threats for rather long durations. We will study possible links between death and coagulation and use lineage tracing models to determine how resident MΦs repopulate. Furthermore, we will investigate the idea that the peritoneal cavity is left susceptible to immunological challenges during the long duration of MΦ loss following MDR. A prolonged period of MΦ loss following a robust MDR may leave the body cavity vulnerable to infection. It may also promote progression of other diseases associated with altered immunity, like cancers. In particular, ovarian cancer is associated with the peritoneal cavity, where it often metastasizes and expands. Human ovarian cancers are considered one of the most procoagulant tumors. If human counterparts to the Factor V+ MΦs exist, which we will study herein, such cells might limit tumor expansion clinically, as observed in mice. Overall, we will test the hypothesis that Factor V+ resident peritoneal macrophages protect the peritoneal cavity from microbial pathogens but also against ovarian tumors and that the procoagulant activity of these macrophages, if linked to MDR by a microbial or inflammatory trigger, may set up a state of enhanced susceptibility to tumor growth due to loss of tumor-restricting MΦs. RELEVANCE (See instructions): Serious clinical conditions can arise in the peritoneal cavity, ranging from the initiation and progression of sepsis to cancer. These diverse conditions rely on a functional immune compartment in the peritoneal space, but there is much that remains to be defined to better combat diseases in this space. This application focuses on host defense mediated by resident peritoneal macrophages.