A major component of many inflammatory diseases of mucosal surfaces, particularly in the intestine, is migration of large numbers of neutrophils (PMN) across the epithelium and accumulation within a lumen. In such conditions, disease symptoms are complex but directly related to leukocyte effects on the epithelial barrier and epithelial cell function. While much has been learned about mechanisms of leukocyte emigration from the circulation, much less is known about the receptors that regulate leukocyte interactions with the intestinal epithelium. Over the past several years, evidence has emerged linking a family of adhesion proteins termed Junctional Adhesion Molecules (JAMs) as important regulators of leukocyte trafficking and barrier function that is consistent with the differential expression of JAMs in populations of leukocytes and epithelial tight junctions. Our studies suggest that expression of the prototypic family member termed JAM-A on leukocytes and epithelial cells is important in preventing pathologic inflammation in the intestine. Furthermore, our recent findings have implicated other JAM-like proteins in mediating transepithelial migration (TEM) of neutrophils in the intestine;however, much less is known about these JAMs. The overall goal of this proposal is to define the role of JAMs in regulating intestinal inflammation by evaluating contributions of leukocyte and epithelial expressed proteins. We will specifically examine effects of JAM-A deficiency on innate immune function and accompanying adaptive immune responses in the intestine. In addition, we will explore the roles of other closely related JAMs in the regulation of neutrophil TEM and barrier function. In addition to gaining insights into the complex molecular basis of the relationship between the intestinal epithelial barrier and specific innate/adaptive immune cell components, it is hoped that these studies will provide new ideas for the development of agents that alter JAM protein function for use as immunomodulatory agents, to manipulate barrier function for drug/vaccine delivery, or cancer therapy.

Public Health Relevance

A characteristic feature of a number of diseases of the gastrointestinal, respiratory, and urinary systems is excessive recruitment and migration of acute inflammatory cells termed neutrophils across a specialized epithelium that lines these organs to form a protective barrier. Proteins that regulate the epithelial barrier termed JAMs have also been shown to play roles in the recruitment and migration of neutrophils, yet the mechanisms linking these disparate JAM functions are not understood. This proposal seeks to characterize the role a prototypic JAM protein termed JAM-A and two related molecules in regulating neutrophil migration in the intestine and the role these proteins play in maintenance of the protective barrier. Understanding the relationships between JAM proteins, epithelial barrier, and inflammation may provide new strategies for organ targeted therapies with a potential benefit of less systemic side effects than those currently available for conditions such as inflammatory bowel disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK072564-20
Application #
8725644
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Perrin, Peter J
Project Start
1995-04-05
Project End
2015-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
20
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Emory University
Department
Pathology
Type
Schools of Medicine
DUNS #
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
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
Lai, Caroline M; Boehme, Karl W; Pruijssers, Andrea J et al. (2015) Endothelial JAM-A promotes reovirus viremia and bloodstream dissemination. J Infect Dis 211:383-93
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 81 publications