Editors' ChoiceINFLAMMATORY BOWEL DISEASE

It Takes Two to Tango: How Phagocytes and Innate Lymphoid Cells Control IBD Outcome

See allHide authors and affiliations

Science Translational Medicine  06 Aug 2014:
Vol. 6, Issue 248, pp. 248ec137
DOI: 10.1126/scitranslmed.3010116

Inflammatory bowel disease (IBD)—including ulcerative colitis (UC) or Crohn’s disease (CD)—is characterized by chronic inflammation of the digestive tract. Environmental and genetic factors both contribute to IBD development, as do enteric bacteria. Because both UC and CD are not medically curable, finding strategies to block chronic inflammatory response is essential. As such, the cellular interactions that occur in the digestive tract need further exploration regarding how they influence IBD outcome.

Longman et al. sought to identify whether the two innate cells—phagocytes and innate lymphoid cells—interact and whether such interaction improves the outcome of IBD. The authors studied the cross-talk between two different cell types: mononuclear phagocytes (MNPs), which act as sentinels of the intestinal lamina propria by responding to microbial products, and type 3 innate lymphoid cells (ILC3s), which help maintain intestinal homeostasis by producing the cytokine interleukin-22 (IL-22) that promotes mucosal healing and maintains barrier integrity. They tested the role of these cells in a model of Clostridium rodentium mouse infection and in patients with colitis. The authors established a mouse model that allows specific depletion of CX3CR1+ MNPs in the gut. Using this model, they observed a reduction of the regulatory cytokine IL-22 specifically in ILC3, but not in conventional T cells. Activation of both Toll-like receptor 4 (TLR4) and TLR9 showed these cells to be potent inducers of IL-23 and IL-1β production by CX3CR1+ MNPs. Using a genome-wide association study analysis, the authors identified that the gene tumor necrosis factor (TNF)–like ligand 1A (TL1A or TNFSF15), which is known to be associated with both UC and CD, is overexpressed in mouse CX3CR1+ MNPs and further amplifies IL-23 and IL-1β induction of IL-22 production in both human and mouse ILC3.

Although other innate cells could also contribute to the development of IL23-producing ILC3s, this study provides important insights regarding the pathogenesis of human IBD. Considering that mucosal ILC3 is known to be a critical player in the maintenance of gut homeostasis and that CX3CR1+ MNPs respond to endogenous microbial ligands to regulate ILC3, these cells may serve as important therapeutic targets.

R. S. Longman et al., CX3CR1+ mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22. J. Exp. Med. 211, 1571–1583 (2014). [Abstract]

Navigate This Article