The long-term objectives of this research application is to better understand the cellular and molecular basis of the inflammatory response in order to develop better therapies to augment it in conditions where the host's immune response is compromised, and to inhibit it under conditions where the response is counterproductive, such as in inflammatory diseases like atherosclerosis, rheumatoid arthritis and other autoimmune diseases, septic shock, asthma, and transplant rejection. A critical step in the inflammatory response is the migration of leukocytes out ofthe bloodstream to the site of inflammation. We have been studying the molecules and mechanisms responsible for diapedesis-the step in this process in which leukocytes pass across the endothelial cells lining postcapillary venules at sites of leukocyte egress. In the first funding period of this grant, we discovered a molecule (CD99) and a mechanism (targeted recycling of membrane from an intemal perijunctional compartment called the LBRC) that play significant roles in diapedesis. In the second funding period thus far (i.e., the first 3.5 years ofthe MERIT award) we have already accomplished most of the Specific Aims of the 5 year plane: We have investigated how CD99 regulates diapedesis. We have discovered that it is present in the LBRC and its function requires the presence of PECAM in the compartment as well. We have cloned the mouse version of CD99 and the related molecule CD99L2 and demonstrated that both play a role in transmigration. We have demonstrated that transcellular migration involves the same mechanism as paracellular migration: Targeted membrane trafficking from the LBRC to the site of migration in a microtubule-dependent manner. The goals for the MERIT extension period are to develop the work proposed for these specific aims to answer the next important questions. These include: What signals from CD99 are required to complete transmigration? Why does CD99 function depend on PECAM? (How do these molecules interact?) Do CD99 and CD99L2 complement each other's function in vivo? If so, how? Is blocking them therapeutic in models of chronic inflammatory disease? How is LBRC membrane recruited for transcellular migration in vitro and in vivo?
Inflammation is the body's response to tissue damage of any kind. It is critical for fighting off infectious microorganisms and healing wounds.^ However, most diseases are due to or exacerbated by inflammation that is out of control, continuing for too long, or in the wrong place at the wrong time. By understanding the molecular basis of inflammation, we will better be able to control it. This will lead to better therapies.
|Sullivan, David P; Watson, Richard L; Muller, William A (2016) 4D intravital microscopy uncovers critical strain differences for the roles of PECAM and CD99 in leukocyte diapedesis. Am J Physiol Heart Circ Physiol 311:H621-32|
|Muller, William A (2016) Transendothelial migration: unifying principles from the endothelial perspective. Immunol Rev 273:61-75|
|Cyrus, Bita F; Muller, William A (2016) A Unique Role for Endothelial Cell Kinesin Light Chain 1, Variant 1 in Leukocyte Transendothelial Migration. Am J Pathol 186:1375-86|
|Muller, William A (2016) Localized signals that regulate transendothelial migration. Curr Opin Immunol 38:24-9|
|Muller, William A (2016) How monocytes guard the glomerulus. Proc Natl Acad Sci U S A 113:10453-5|
|Winger, Ryan C; Harp, Christopher T; Chiang, Ming-Yi et al. (2016) Cutting Edge: CD99 Is a Novel Therapeutic Target for Control of T Cell-Mediated Central Nervous System Autoimmune Disease. J Immunol 196:1443-8|
|Maisa, Anna; Hearps, Anna C; Angelovich, Thomas A et al. (2015) Monocytes from HIV-infected individuals show impaired cholesterol efflux and increased foam cell formation after transendothelial migration. AIDS 29:1445-57|
|Feng, Gong; Sullivan, David P; Han, Fei et al. (2015) Segregation of VE-cadherin from the LBRC depends on the ectodomain sequence required for homophilic adhesion. J Cell Sci 128:576-88|
|Watson, Richard L; Buck, Jochen; Levin, Lonny R et al. (2015) Endothelial CD99 signals through soluble adenylyl cyclase and PKA to regulate leukocyte transendothelial migration. J Exp Med 212:1021-41|
|Weber, Evan W; Han, Fei; Tauseef, Mohammad et al. (2015) TRPC6 is the endothelial calcium channel that regulates leukocyte transendothelial migration during the inflammatory response. J Exp Med 212:1883-99|
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