The Role of Tissue Transglutaminase 2 in the Modulation of Polymorphonuclear Leukocyte Function

Abstract

Inflammatory Bowel Disease is mostly represented by Crohn's Disease and Ulcerative Colitis. The disease presents as a series of inflammatory disorders that involves dysregulated neutrophil (PMN) migration across the intestinal epithelium. Tissue Transglutaminase (TGM) 2 is an enzyme that catalyzes calcium‐dependent crosslinks of amino groups and has been implicated in a variety of cellular functions including cell growth and wound healing, which involves GTPase mediated activities (shown to affect PMN adhesion). TGM 2 antibodies are present in the small intestine of patients with Celiac Disease (diet induced inflammation in the small intestine) and a majority of Crohn's Disease patients also have Celiac Disease. Despite these observations, the role of TGM 2 in PMN activities has not been widely explored. We determined that TGM 2 has an extracellular and intracellular localization in PMN and appears to inhibit translocation of CD11b (activating integrin of PMN) to the surface of PMN. TGM 2 can inhibit PMN attachment to fibrinogen (a ligand for CD11b) by approximately 50% and can inhibit fMLP‐directed PMN migration by approximately 50%, which strongly suggests that TGM 2 may be connected to CD11b mediated events. The fMLP receptor is a G‐protein coupled (7TM spanning) receptor that regulates PMN response by an up‐regulation of adhesion and migration receptors. Using Flow Cytometry, we determined that TGM 2 affects PMN adhesion and migration through the PMN fMLP receptor. These data highlight TGM 2 as a potential target in the treatment of mucosal inflammation involving aberrant PMN migration.