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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Perrin, Peter J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Emory University
Schools of Medicine
United States
Zip Code
Flemming, Sven; Luissint, Anny-Claude; Nusrat, Asma et al. (2018) Analysis of leukocyte transepithelial migration using an in vivo murine colonic loop model. JCI Insight 3:
Quiros, Miguel; Nishio, Hikaru; Neumann, Philipp A et al. (2017) Macrophage-derived IL-10 mediates mucosal repair by epithelial WISP-1 signaling. J Clin Invest 127:3510-3520
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
Azcutia, Veronica; Parkos, Charles A; Brazil, Jennifer C (2017) Role of negative regulation of immune signaling pathways in neutrophil function. J Leukoc Biol :
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
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
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
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
Brazil, Jennifer C; Parkos, Charles A (2016) Pathobiology of neutrophil-epithelial interactions. Immunol Rev 273:94-111

Showing the most recent 10 out of 87 publications