The epithelium separates the vast array of luminal antigens from the underlying gastrointestinal tissue and in this position, it serves as the first site to encounter many pathogens. Epithelial cells emerge from stem cells from the deeper layers of the glands which differentiate as they migrate towards the lumen. After reaching the top of the gland or villous, epithelial cells die and either slough into the lumen or get engulfed by phagocytes within the lamina propria. Antigen presenting cells (APC), including macrophages and dendritic cells, can remove bacteria, cellular debris and dead cells through phagocytosis or autophagy. Engulfment of apoptotic cells is generally anti- inflammatory since it stimulates the release of TGF-?. The importance of proper phagocytosis in the control of gastrointestinal inflammation is supported by the fact that mice deficient in a receptor for apoptotic cells develop colitis. In contrast, cells that undergo apoptosis when they carry an intracellular infection with Salmonella enterica serovar Typhimurium may act as a microbial """"""""Trojan horse"""""""" that transports internalized bacteria into the APC thereby stimulating inflammatory responses. Thus, I hypothesize that apoptotic epithelial cells are recognized and engulfed by antigen presenting cells and this process modulates local inflammatory responses. Specifically, I propose to determine if engulfment of human epithelial cells rendered apoptotic in the absence of intracellular infections are actively anti-inflammatory while uptake of infected corpses favors the induction of inflammation. The objective of this proposal is to define the molecular basis governing the recognition and engulfment of apoptotic cells throughout the human gastrointestinal tract and the impact of this process on immune regulation. These objectives will be achieved in the following Specific Aims:
Aim 1 : Define which structures recognize apoptotic epithelial cells in the gut.
Aim 2 : Examine the signaling events that regulate the engulfment of epithelial cell corpses.
Aim 3 : Examine the role of bacterial proteins in regulating Rac1 activation and mucosal inflammation. Although many aspects of innate immunity have been studied, little is known about the mechanisms of apoptotic, epithelial cell engulfment in the human digestive tract and their impact on local host responses. This gap in our knowledge makes the proposed studies an exciting new frontier with broad relevance for mucosal immunity in humans. This proposal will examine the mechanisms by which phagocytes mediate the engulfment of apoptotic epithelial cells and how this process impacts mucosal inflammation. Establishing a novel role for engulfment and the receptors involved in this process will lead to future translational studies that model this process in the human digestive tract. This new information may have therapeutic applications for the prevention or treatment of digestive diseases triggered by infection including inflammatory bowel diseases and infectious diarrhea.
This proposal will examine the mechanisms by which phagocytes mediate the engulfment of apoptotic epithelial cells and how this process impacts mucosal inflammation. Establishing a novel role for engulfment and the receptors involved in this process will lead to future translational studies that model this process in the human digestive tract. This new information may have therapeutic applications for the prevention or treatment of digestive diseases triggered by infection including inflammatory bowel diseases and infectious diarrhea.
| Mauldin, Joshua P; Lu, Mingjian; Das, Soumita et al. (2013) A link between the cytoplasmic engulfment protein Elmo1 and the Mediator complex subunit Med31. Curr Biol 23:162-7 |
