Formyl Peptide Receptor-1 Activation Enhances Intestinal Epithelial Cell Restitution through Phosphatidylinositol 3-Kinase-Dependent Activation of Rac1 and Cdc42

Abstract

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.

The Leukocyte Chemotactic Receptor FPR1 Is Functionally Expressed on Human Lens Epithelial Cells

“…Beas2B lung epithelial cells (14), SK-CO15 intestinal epithelial cells (15,16), MKN-28 and AGS gastric epithelial cells (17), and human retinal pigment epithelial cells (18). Several papers (14,16,18) report that FPR1 agonists induced an FPR1 antagonist-sensitive acceleration of wound healing in an in vitro model using a scratch-injured cell monolayer. Mostly, FPR1 was investigated either in cancer cells or in non-cancerous tissues under in vitro conditions.…”

Mucosal Immunity and the Microbiome

“…Formylated peptide receptor (FPR) stimulation occurs with both pathogenic and symbiotic bacteria. Importantly, immunohistochemical staining has shown the FPRs are expressed not solely on phagocytes, but also on the apical surface of the intestinal and airway epithelia, prompting interest that this and related epithelial receptors may mediate physiological responses in mucosal tissues (27). Phagocytes generate ROS via a well-studied enzymatic apparatus.…”

Helicobacter pylori Hp(2–20) Promotes Migration and Proliferation of Gastric Epithelial Cells by Interacting with Formyl Peptide Receptors In Vitro and Accelerates Gastric Mucosal Healing In Vivo

“…We therefore tested whether fMLP and Hp (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) could also induce cell proliferation. To address this point, we mea- …”

“…Since the natural source of these peptides is bacteria, and FPRs are expressed in abundance by cells of the host defense system (e.g., neutrophils), a view emerged that the FPR family has evolved as chemoattractant receptors that assist the organism in counteracting bacterial infections, in particular by facilitating the trafficking of phagocytes to the site of bacterial invasion (5,6). Moreover, FPRs also participate in essential pathophysiologic processes, including intestinal epithelial cell restitution (7). Whether FPRs are expressed in gastric epithelial cells and whether they play a role in the healing of injured gastric mucosa remain uncertain.…”

“…Therefore, this study was designed: (1) to assess whether gastric epithelial cell lines express FPRs; (2) to investigate whether Hp (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) stimulates cell migration and proliferation and VEGF expression and release in gastric epithelial cell lines; (3) to investigate the role of FPRs in any such effect(s); and (4) to evaluate whether Hp (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) accelerates healing in a rat model of indomethacin-induced gastric mucosal damage.…”