Promoting MΦ transepithelial migration by stimulating the epithelial cell P2Y2 receptor

In intestine, neutrophils are recruited in response to bacterial infiltration and their anti‐cellular activities contribute to inflammatory bowel diseases. In contrast, little is known regarding the recruitment of MΦ to the intestinal epithelium. Extracellular adenosine and uridine 5′‐triphosphate (ATP and UTP) can function as leukocyte chemoattractants. We investigated the effects of these nucleotides on the ability of intestinal epithelial cells (IEC) to promote MΦ transepithelial migration and adhesion. ATP and UTP promoted the migration of neutrophil‐like PLB‐985 cells and MΦ across a Caco‐2 monolayer. The MΦ‐like U‐937 cells adhered to nucleotide‐stimulated IEC monolayers. In mice with intestinal inflammation, there were infiltrating CD68⁺ MΦ in the colonic epithelium and CD68⁺ MΦ present at the apical surface of colonocytes. We determined that ATP and UTP activated the P2Y₂ receptor P (P2Y₂R) to increase ICAM‐1 expression, which mediated the adhesion of MΦ to the apical surface of IEC. Intriguingly, stimulation of IEC with nucleotides did not increase the adhesion of neutrophils. However, in the presence of adherent MΦ, there was adhesion of neutrophils, suggesting that MΦ may serve as anchors for neutrophil adhesion. These studies provide insight into the inflammatory mechanisms that contribute to inflammatory bowel diseases and identify potential therapeutic targets for the treatment of gastrointestinal disorders.