Functional characterization of JAM-A in neutrophil transepithelial migration during intestinal mucosal inflammation

• Applicant: Privatdozent Dr. Sven Flemming
• Subject Area: General and Visceral Surgery
• Term: from 2016 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 329865901

Inflammatory Bowel Disease (IBD) encompassing Crohns disease and ulcerative colitis are chronic relapsing disorders. The etiology of IBD is multifactorial and remains incompletely understood; however trigger factors are driven by genetic predisposition, environmental factors and mucosal epithelial barrier dysfunction that lead to dysregulated immune responses against microflora-derived antigens and massive recruitment of neutrophils (PMN) (first responders of innate immunity against bacteria) into the intestinal mucosa. The migration of PMN across the single layer of epithelial cells (IECs) that covers the intestinal mucosa is a multiple step process that includes PMN adhesion to the basal membrane of IECs, migration between IECs and interactions at the apical epithelial surface at the intestinal lumen. PMN migration between IECs (paracellular migration) involves crossing epithelial intercellular junction protein complexes, desmosomes, adherens junction and tight junction (TJ) that are sequentially localized from the basal membrane to apical side. However, in contrast to PMN migration across the endothelial barrier (transendothelial migration) the molecular mechanisms involved in PMN in transepithelial migration (TEpM) remain to be elucidated. A TJ associated transmembrane protein termed Junctional Adhesion Molecule-A (JAM-A) has been shown to play an important role in the maintenance of epithelial barrier function and regulate PMN migration across vascular endothelium [1]. JAM-A is also expressed on leukocytes including PMN, however, the specific contributions of epithelial versus leukocyte JAM-A in controlling TEpM are unclear and require further investigation. The overall goal of this proposal is to decipher the role of JAM-A in PMN TEpM during intestinal mucosal inflammation such as IBD using in-vivo approaches. This study will help to better characterize the molecular interactions between IECs and PMN that are involved in the PMN TEpM process. Furthermore, it will provide new insights for therapeutic strategies that aim to decrease immune responses in inflammatory disorders.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Charles Parkos, Ph.D.