Neutrophil Regulation of Colitis

The delicate intestinal homeostasis is regulated by interactions between microbiota, intestinal epithelial cells (IECs), and the intestinal immune system. As a crucial component of the innate immune system, neutrophils are the first responders to sites of inflammation when the intestinal epithelial barrier is breached and gut microbiota invade. Although accumulation of neutrophils in the intestine is correlated with inflammatory bowel disease (IBD), the relative contributions of neutrophils to the pathogenesis of IBD are still controversial. It has been shown that neutrophils are active producers of both IL-22 and IL-17, which differentially regulate the pathogenesis of IBD. Our current studies indicate that IL- 22-producing neutrophils play a crucial role in colitis. We showed that IL-23 can promote neutrophil production of IL-17 and IL-22. IL-23 signals through its receptors and further upregulates its own receptors. Subsequently, IL-23 activates the PI3K-mTOR pathway, which mediates the expression of retinoid acid receptor–related orphan receptor g t (RORγt) and aryl-hydrocarbon receptor (AhR). Neutrophils can also produce TGFβ to regulate IEC functions. Neutrophil-derived TGFβ activates MEK1/2 signaling in IECs enhancing the production of amphiregulin (AREG), a member of EGFR ligand family. Upon the induction of an intestinal inflammatory state, AREG signals through the EGFR pathway to induce epithelial junction formation, as a way to restore epithelial function and ameliorate colitis. Taken together, our studies reveal a previously unappreciated immune regulatory role of neutrophils in coordination with IECs to maintain and/or restore gut homeostasis. Given further research, these findings could ultimately lead to the development of novel targeted treatments for IBD and other autoimmune diseases.