Neutrophils (PMN) are the first responders to the intestinal mucosa during an acute inflammatory response. In addition to playing a critical role in clearing invading microorganisms, infiltrating PMN mediate both mucosal injury and repair. These diverse functions are dependent, in part, on efficient recruitment and migration in concert with death and clearance of "used" PMN. While much is known about the mechanisms regulating chemotaxis, microbicidal, and tissue functions of PMN, there are considerable gaps in the understanding of mechanisms regulating recruitment of PMN to the intestine in-vivo. Furthermore, the role(s) of PMN in maintenance of mucosal homeostasis is not well understood. Over the past two decades, a number of membrane proteins have been identified that play key roles in regulating migration and other key functions of PMN. One such protein termed CD47 is abundantly expressed in PMN and most other cells of the body. Depending on the type of cell that expresses it, CD47 has been implicated in a diverse set of functions. In PMN, we and others have shown that CD47 plays important roles in regulation of migration and phagocytosis however how it mediates function in the context of tissue (intestine) responses remains poorly defined. In this proposal, we will extend in-vivo experimental results that highlight intrinsic and extrinsic roles for CD47 in regulating the rate of PMN recruitment, tissue injury and clinical responses in models of acute and chronic intestinal inflammation. Furthermore, we will pursue studies directed at elucidating how CD47 regulates death and clearance of PMN. From these proposed studies, we will define the contributions of PMN and epithelial- derived CD47 to the regulation of the rate of PMN recruitment and intestinal mucosal homeostasis. It is hoped that these studies will provide new ideas for the development of agents that can exploit CD47-dependent function to attenuate pathologic inflammation and promote mucosal healing.

Public Health Relevance

Regulated recruitment and migration of acute inflammatory cells termed neutrophils (PMN) into the intestine and across the specialized epithelium that lines it is critical for host defense, yet dysregulation of this process is associated with disease. The goal of this proposal is to define the relative contributions of PMN and epithelial cells to the function of a protein termed CD47 in the regulation of acute intestinal inflammation. These studies should provide new ideas for the development of agents that can exploit CD47-dependent function to attenuate pathologic inflammation and the consequences of such.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK079392-10A1
Application #
8761789
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Grey, Michael J
Project Start
2002-10-01
Project End
2019-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
10
Fiscal Year
2014
Total Cost
$468,511
Indirect Cost
$167,012
Name
Emory University
Department
Pathology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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
Parkos, Charles A (2016) Neutrophil-Epithelial Interactions: A Double-Edged Sword. Am J Pathol 186:1404-16
Brazil, Jennifer C; Parkos, Charles A (2016) Pathobiology of neutrophil-epithelial interactions. Immunol Rev 273:94-111
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
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
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
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
Sumagin, R; Brazil, J C; Nava, P et al. (2016) Neutrophil interactions with epithelial-expressed ICAM-1 enhances intestinal mucosal wound healing. Mucosal Immunol 9:1151-62
Newman, K L; Moe, C L; Kirby, A E et al. (2015) Human norovirus infection and the acute serum cytokine response. Clin Exp Immunol 182:195-203
Leoni, Giovanna; Gripentrog, Jeannie; Lord, Connie et al. (2015) Human neutrophil formyl peptide receptor phosphorylation and the mucosal inflammatory response. J Leukoc Biol 97:87-101

Showing the most recent 10 out of 56 publications