A key challenge at the intestinal barrier is to minimize responses to commensal bacteria, which can lead to inflammatory bowel disease (IBD) in genetically predisposed individuals, but retain the ability to recognize and control the growth of infectious pathogens. Group 3 innate lymphoid cells (ILC3) help maintain intestinal homeostasis by producing the cytokine IL-22, which promotes mucosal healing and maintains barrier integrity. Microbial signals trigger production of IL-23 and IL-1β, which stimulate ILC3s to produce IL-22, leading to the induction of antibacterial peptides and epithelial cell regeneration.

But the identity of the cell type producing IL-23 in response to microbial signals is unclear and has been the subject of much debate; resident mononuclear phagocytes, inflammatory monocytes, and conventional dendritic cells have all been implicated. In this issue, Longman et al. provide compelling evidence, both in mouse following Citrobacter rodentium infection and in patients with colitis, that CX3CR1+ mononuclear phagocytes (MNPs) are the most potent producers of IL-23 and IL-1β and are very efficient in inducing IL-22 production by ILC3.

The authors demonstrated the importance of microbial stimulation in IL-22 induction in patients with surgical diversion of the fecal stream—IL-22 production by ILC3 was lower in the sites unexposed to the gut microbiota compared with exposed sites. Microbial TLR4 and TLR9 agonists were particularly efficient at inducing IL-23 and IL-1β production by CX3CR1+ MNPs. The authors also discovered that a gene significantly associated with both ulcerative colitis and Crohn’s disease in GWAS, TNF-like ligand 1A (TL1A or TNFSF15), is overexpressed in mouse CX3CR1+ MNPs and synergizes with IL-23 and IL-1β to induce IL-22 production in both human and mouse ILC3.

The study does not completely exclude the role of other cell types in the production of IL-23 and induction of IL-22 production but in the conditions studied (mouse infection with C. rodentium and human colitis), CX3CR1+ MNPs were crucial in mediating this mucosal protective loop. In basal conditions or in other types of inflammatory or preneoplastic conditions, and under stimulation by different microbial TLR agonists (e.g., flagellin), it is quite possible that other cell types, including conventional dendritic cells, may play an important role, as suggested by published studies. However, the study by Longman et al. greatly contributes to our understanding of the mechanisms of human IBD and reassures us that when mouse data are carefully combined with experimental human studies and GWAS, they are powerful in providing mechanistic evidence that explains human pathology.

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J. Exp. Med.