Commensal-Epithelial Signaling Mediated via Formyl Peptide Receptors

Commensal bacteria and/or their products engender beneficial effects to the mammalian gut including stimulating physiological cellular turnover and enhancing wound healing without activating overt inflammation In the present study we observed commensal bacteria mediated activation of the noninflammatory extracellular signal regulated kinase[ERK]/mitogen activated protein kinase and Ala signaling pathways in gut epithelial cells and delineated a mechanism for this bacterially activated signaling All tested strains of commensal bacteria induced ERK phosphorylation without stimulating pro-inflammatory phospho-I kappa B or pro-apoptotic phos pho-c Jun NH2 terminal kinase with Lactobacillus species being most potent. This pattern of signaling activation was recapitulated using the peptide N formyl Met Leu Phe a bacterial product known to stimulate signaling events in mammalian phagocytes Sensing of N formyl Met Leu Phe by gut epithelial cells occurs via recently characterized formyl peptide receptors located in the plasma membrane Both commensal bacteria and N formyl Met Leu Phe application to the apical surface of polarized gut epithelial cells resulted in specific formyl peptide receptor activation. In addition, pretreatment of model epithelia and murine colon with Boc2 (a specific peptide antagonist) or pertussis toxin (a G(1) protein inhibitor) abolished commensal mediated ERK phosphorylation Taken together these data show that commensal bacteria specifically activate the ERK/mitogen activated protein kinase pathway in an formyl peptide receptor-dependent manner delineating a mechanism by which commensal bacteria con tribute to cellular signaling in gut epithelia. (Am J Pathol 2010 177 2782-2790 DOI 10 2353/ajpath 2010 100529)