The epithelium separates the vast array of luminal antigens from the underlying gastrointestinal tissue and from this position;it serves as the first site to encounter many pathogens. Gastric epithelial cells emerge from stem cells within the deeper regions of the glands that differentiate as they migrate towards the lumen. After reaching the top of the foveolar pits, 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-b. 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. However, nobody has ever studied the outcome of engulfment in normal or inflamed gastric tissue during H. pylori infection when epithelial cell apoptosis is increased. Macrophages isolated from human gastrointestinal mucosa are hyporesponsive. However, during chronic inflammation, gastrointestinal APC cells lose this hyporesponsiveness and contribute to the inflammation. The hypothesis being tested is that apoptotic gastric epithelial cells are recognized and engulfed by antigen presenting cells and this process modulates local inflammatory responses. Specifically, I will determine if the outcome human epithelial cell engulfment modulates inflammation associated with H. pylori infection. The objective of this application is to define the molecular basis for the recognition and engulfment of apoptotic cells in the human stomach and to assess the impact of this process on immune regulation in health and disease. This will be examined in the following Specific Aims:
Aim 1 : Evaluate the receptors contributing to the internalization of apoptotic epithelial cells.
Aim 2 : Define the downstream responses that regulate the engulfment of epithelial cell corpses.
Aim 3 : Examine the molecular basis by which engulfment regulates gastric inflammation.
Aim 4 : Determine the expression and function of engulfment molecules in the human stomach. 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 and gastric immunobiology in particular.

Public Health Relevance

This application will examine the mechanisms whereby phagocytes internalize apoptotic gastric epithelial cells and how the engulfment of apoptotic epithelial cells impacts gastritis. These studies also provide a translational component that will investigate this process directly in the human stomach. This new information may have broader therapeutic applications for the prevention or treatment of digestive diseases triggered by infection including gastritis, inflammatory bowel diseases and infectious diarrhea.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK084063-03
Application #
8333301
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Hamilton, Frank A
Project Start
2010-05-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$403,909
Indirect Cost
$93,587
Name
University of California San Diego
Department
Pathology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Das, Soumita; Sarkar, Arup; Ryan, Kieran A et al. (2014) Brain angiogenesis inhibitor 1 is expressed by gastric phagocytes during infection with Helicobacter pylori and mediates the recognition and engulfment of human apoptotic gastric epithelial cells. FASEB J 28:2214-24
Bimczok, Diane; Smythies, Lesley E; Waites, Ken B et al. (2013) Helicobacter pylori infection inhibits phagocyte clearance of apoptotic gastric epithelial cells. J Immunol 190:6626-34
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
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Das, Soumita; Owen, Katherine A; Ly, Kim T et al. (2011) Brain angiogenesis inhibitor 1 (BAI1) is a pattern recognition receptor that mediates macrophage binding and engulfment of Gram-negative bacteria. Proc Natl Acad Sci U S A 108:2136-41
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Shen, Ruizhong; Richter, Holly E; Smith, Phillip D (2011) Early HIV-1 target cells in human vaginal and ectocervical mucosa. Am J Reprod Immunol 65:261-7
Shen, Ruizhong; Meng, Gang; Ochsenbauer, Christina et al. (2011) Stromal down-regulation of macrophage CD4/CCR5 expression and NF-*B activation mediates HIV-1 non-permissiveness in intestinal macrophages. PLoS Pathog 7:e1002060

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