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* Epithelial Pathobiology Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322; and
Department of Microbiology, Montana State University, Bozeman, MT 59715
Inflammatory disorders of the gastrointestinal tract result in the breakdown of the intestinal epithelial barrier in the form of erosion and ulceration. To reestablish the epithelial barrier, the epithelium must efficiently migrate to reseal wounds. Numerous signaling cascades are involved in the induction and regulation of this complex process. N-formyl peptide receptors comprise a group of Gi-coupled receptors that regulate innate immune responses. Previously, we identified the expression of functional N-formyl peptide receptors in model SK-CO15 intestinal epithelial cells and observed a role for activation of these receptors in regulating cellular invasive behavior. In these studies, we performed formyl peptide receptor-1 (FPR) localization and evaluated its role in regulating intestinal epithelial cell wound closure. Immunolocalization studies using a recently developed specific monoclonal anti-FPR Ab demonstrated its localization along the lateral membrane of crypt epithelial cells in normal human colonic epithelium. In vitro studies using the classical FPR agonist fMLF showed that FPR activation significantly enhances model intestinal epithelial cell restitution and that FPR localized along actin filaments in lamellipodial and filopodial extrusions. The increase in cell migration was associated with activation of PI3K, Rac1, and Cdc42. Pharmacologic inhibition of PI3K activity abrogated the fMLF-induced increase in wound closure and activation of both Rac1 and Cdc42. Inhibition of Rac1 and Cdc42 using pharmacologic inhibitors and dominant negative mutants also inhibited the fMLF-induced increase in cell migration. Taken together, theses results support a novel role for FPR stimulation in enhancing intestinal epithelial cell restitution through PI3K-dependent activation of Rac1 and Cdc42.
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1 This work was supported by National Institutes of Health Career Development Award K08 DK074706-01 (to B.A.B.), a career development award from the Crohn’s and Colitis Foundation of America (to A.I.I.), Digestive Disease Minicenter Grant DK 064399, Public Health Service RO1 Awards AI22735 and AI26711 (to A.J.J.), DK61379, HL72124, and DK72564 (to C.A.P.), and DK55679 and DK59888 (to A.N.).
2 Address correspondence and reprint requests to Dr. Brian A. Babbin or Dr. Asma Nusrat, Department of Pathology and Laboratory Medicine, Emory University, Whitehead Biomedical Building, 615 Michael Street, Atlanta, GA 30322. E-mail addresses: bbabbin{at}emory.edu and anusrat{at}emory.edu
3 Abbreviations used in this paper: GPCR, G protein-coupled receptor; Boc, N-tert-butoxycarbonyl-Met-Leu-Phe; EGFP, enhanced GFP; FPR, formyl peptide receptor-1; FPRL1, formyl peptide receptor-like-1; GEF, guanine nucleotide exchange factor; IEC-6, intestinal epithelial cell line; MLB, magnesium lysis buffer; NFPR2, mouse anti-FPR mAb.
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