The gastrointestinal epithelium functions as a dynamic barrier that serves as an interface between luminal contents and underlying tissue compartments, and is thus vital in maintaining mucosal homeostasis. Mucosal wounds have been observed following enteric infection, inflammatory bowel disease and ischemic insults. Disruption of the critical epithelial barrier allows access of luminal contents to immunologically privileged compartments thereby contributing to disease pathogenesis. In response to injury, intestinal epithelial cells (IEC) migrate and proliferate to rapidly cover denuded surfaces and re-establish the epithelia barrier. We have recently identified expression of the N-formyl peptide receptors (FPR1 and FPR2) in the intestinal epithelium. Our studies determined that a bacterial derived N-formyl peptide, fMLF and the endogenous Annexin 1 protein, which are agonists for FPR family members, promote intestinal epithelial cell migration and facilitate wound closure. Additionally, it is becoming evident that a healthy optimized intestinal microflora mediates important roles in normal gut homeostasis and recovery from mucosal insults. Recent experimental results in our laboratory revealed that epithelial cells exposed to fMLF and intact bacteria also rapidly initiate cytoplasmic signaling events, Rac and Cdc2 activation, reactive oxygen species (ROS) production, epithelial cell migration and wound closure. Thus, we believe that FPRs represent important novel type of pattern recognition receptors (PRR) in the intestinal epithelium that transmit homeostatic signaling and facilitate epithelial barrier recovery following pathologic insults. Thus, our overall objectives are to define the pathobiologic function of epithelial FPRs and microbiota in regulating intestinal homeostasis, barrier recovery and resolution of inflammation.

Public Health Relevance

Intestinal epithelial injury occurs in a wide spectrum of clinical conditions that include inflammatory bowel diseases, enteric infection, ischemia and following surgical procedures. The loss of epithelial barrier function associated with injury contributes to mucosal inflammation. Numerous physiological processes including those influenced by the normal prokaryotic microbiota have been implicated in regulating intestinal epithelial homeostasis. Thus, given the pathologic ramifications of epithelial injury, it is vital to understand mechanisms of intestinal epithelial barrier maintenance/recovery and in defining the role of microbiota in these processes. We propose the formyl peptide receptors (FPRs) as novel pattern recognition receptors that regulate intestinal epithelial growth, motility and restitution post injury, as well as the positive influence of the microbiota in these events. Realization of the role of FPRs and their ligands on epithelial barrier regulation and wound recovery will facilitate in development of therapeutic agents to promote regeneration of the intestinal mucosa.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK089763-03
Application #
8490714
Study Section
Special Emphasis Panel (ZRG1-DKUS-B (04))
Program Officer
Grey, Michael J
Project Start
2011-09-01
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
3
Fiscal Year
2013
Total Cost
$386,110
Indirect Cost
$137,007
Name
Emory University
Department
Pathology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Leoni, Giovanna; Alam, Ashfaqul; Neumann, Philipp-Alexander et al. (2013) Annexin A1, formyl peptide receptor, and NOX1 orchestrate epithelial repair. J Clin Invest 123:443-54
Brazil, Jennifer C; Liu, Renpeng; Sumagin, Ronen et al. (2013) *3/4 Fucosyltransferase 3-dependent synthesis of Sialyl Lewis A on CD44 variant containing exon 6 mediates polymorphonuclear leukocyte detachment from intestinal epithelium during transepithelial migration. J Immunol 191:4804-17