The regulation of inflammation and phagocytosis by CD93

Indiana University Indianapolis, Indianapolis IN

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Abstract

Abstract While inflammation is a normal, protective response to injury, it is becoming increasingly clear that uncontrolled inflammation is integral to most disease processes including cancer and heart disease, the leading causes of death in the United States. The resolution phase of inflammation is an active process involving downmodulation of proinflammatory mediators and clearance of dead or dying cells. Understanding the molecular mechanisms involved in the resolution of inflammation will provide a framework from which to design directed therapeutics to prevent or diminish aberrant inflammation. Rapid and efficient removal of apoptotic cells is critical to the resolution of inflammation. CD93 is a cell surface molecule required for ingestion of apoptotic cells in vivo and is expressed by myeloid cells, platelets and endothelial cells: those cell types principally involved in regulation of inflammation. It belongs to the Group XIV family of transmembrane C-type lectin-like domain (CTLD) containing glycoproteins with shared functions in adhesion, migration and inflammation. We have recently identified a soluble form of CD93 that is elevated in inflammatory fluids. This proposal tests the hypothesis that CD93 regulates monocyte/macrophage activation extracellularly via its membrane tethered or soluble ectodomain, as well as intracellularly via protein and lipid interaction with the intracellular tail. Specifically, the role of CD93 in regulating inflammation in vivo will be assessed in a sepsis model using both CD93-/- mice and mice double deficient in CD93 and TM-D1, a CD93 homologue that downregulates inflammation in sepsis. Soluble CD93 will be tested for its ability to enhance ingestion of apoptotic cells and gram negative bacteria by primary human and mouse phagocytes. Anti-inflammatory properties of sCD93 will be investigated and compared to TM-D1. Membrane tethered CD93 regulates phagocytosis and adhesion in vitro, critical processes in the regulation of inflammation. Previous studies that have identified specific CD93 cytoplasmic tail interacting molecules known to be involved in cytoskeletal dynamics, such as those required for phagocytosis and adhesion, will be extended. Localization and function of these molecules during the phagocytic process will be assessed. These studies will contribute to our understanding of inflammation, and may lead to CD93 directed therapeutics to regulate this process.