Neutrophil (PMN) migration in the gastrointestinal mucosa is a central component of both host defense and pathophysiologic processes such as inflammatory bowel disease (IBD). While many studies have focused on defining events involved in the regulation of PMN migration at the level of cell adhesion, events that serve to regulate the rate with which PMN migrate through intestinal mucosa during the inflammatory response are poorly understood. Studies from our group have demonstrated important contributions from epithelial and PMN expressed membrane proteins which, upon ligation, initiate signals that have profound effects on the kinetics on PMN transmigration. This proposal will focus on a receptor-ligand pair termed CD47-SIRPalpha and a class of proteins termed protease activated receptors (PARs) that are differentially expressed in the intestinal mucosa and on leukocytes and modulate the rate of PMN transmigration through distinct effects on PMN and epithelial cells. We have observed that exposure of migrating PMN to gut-derived microbial products have profound effects on transmigration that may be linked in part to CD47 mediated signaling and in part to PMN stimulated alterations in epithelial permeability through PARs. Our overall goal is to understand the mechanisms of how CD47, SIRP and PARs regulate PMN transmigration in the gut on a structural and functional basis. To achieve this goal we will perform studies employing in vitro methods in concert with murine models of acute colitis to define the contribution(s) of intestinal epithelial and PMN expressed CD47 and potential crosstalk with TLRs on the rate of PMN transepithelial migration, determine structural elements in SIRPalpha that mediate ligand binding/ protein interactions and investigate the role of PMN-epithelial signaling through PARs in regulating the rate of PMN migration across intestinal epithelium. Understanding basic mechanisms regulating the rate of PMN migration across epithelia may provide clues to the pathophysiology of mucosa! diseases such as IBD and aid in the development of new therapeutic strategies aimed at diminishing enhanced permeability and mucosal injury associated with these conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK079392-08
Application #
7848943
Study Section
Special Emphasis Panel (ZRG1-DIG-C (03))
Program Officer
Hamilton, Frank A
Project Start
2002-10-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
8
Fiscal Year
2010
Total Cost
$416,942
Indirect Cost
Name
Emory University
Department
Pathology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Azcutia, Veronica; Bassil, Ribal; Herter, Jan M et al. (2017) Defects in CD4+ T cell LFA-1 integrin-dependent adhesion and proliferation protect Cd47-/- mice from EAE. J Leukoc Biol 101:493-505
Brazil, Jennifer C; Sumagin, Ronen; Stowell, Sean R et al. (2017) Expression of Lewis-a glycans on polymorphonuclear leukocytes augments function by increasing transmigration. J Leukoc Biol 102:753-762
Brazil, Jennifer C; Sumagin, Ronen; Cummings, Richard D et al. (2016) Targeting of Neutrophil Lewis X Blocks Transepithelial Migration and Increases Phagocytosis and Degranulation. Am J Pathol 186:297-311
Gómez-Suárez, M; Gutiérrez-Martínez, I Z; Hernández-Trejo, J A et al. (2016) 14-3-3 Proteins regulate Akt Thr308 phosphorylation in intestinal epithelial cells. Cell Death Differ 23:1060-72
Medina-Contreras, Oscar; Harusato, Akihito; Nishio, Hikaru et al. (2016) Cutting Edge: IL-36 Receptor Promotes Resolution of Intestinal Damage. J Immunol 196:34-8
Luissint, Anny-Claude; Parkos, Charles A; Nusrat, Asma (2016) Inflammation and the Intestinal Barrier: Leukocyte-Epithelial Cell Interactions, Cell Junction Remodeling, and Mucosal Repair. Gastroenterology 151:616-32
Butin-Israeli, Veronika; Houser, Madelyn C; Feng, Mingli et al. (2016) Deposition of microparticles by neutrophils onto inflamed epithelium: a new mechanism to disrupt epithelial intercellular adhesions and promote transepithelial migration. FASEB J 30:4007-4020
Matthews, Jason D; Sumagin, Ronen; Hinrichs, Benjamin et al. (2016) Redox control of Cas phosphorylation requires Abl kinase in regulation of intestinal epithelial cell spreading and migration. Am J Physiol Gastrointest Liver Physiol 311:G458-65
Brazil, Jennifer C; Parkos, Charles A (2016) Pathobiology of neutrophil-epithelial interactions. Immunol Rev 273:94-111
Newman, K L; Moe, C L; Kirby, A E et al. (2016) Norovirus in symptomatic and asymptomatic individuals: cytokines and viral shedding. Clin Exp Immunol 184:347-57

Showing the most recent 10 out of 60 publications