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CX₃CR1⁺ mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22.

TitleCX₃CR1⁺ mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22.
Publication TypeJournal Article
Year of Publication2014
AuthorsLongman RS, Diehl GE, Victorio DA, Huh JR, Galan C, Miraldi ER, Swaminath A, Bonneau R, Scherl EJ, Littman DR
JournalJ Exp Med
Date Published2014 Jul 28
KeywordsAnimals, Citrobacter rodentium, Colitis, Dendrites, Feces, Humans, Immunity, Innate, Interleukin-1beta, Interleukin-23, Interleukins, Intestinal Mucosa, Lymphocytes, Mice, Monocytes, Phagocytes, Receptors, Chemokine, Toll-Like Receptors, Tumor Necrosis Factor Ligand Superfamily Member 15

Interleukin (IL)-22-producing group 3 innate lymphoid cells (ILC3) promote mucosal healing and maintain barrier integrity, but how microbial signals are integrated to regulate mucosal protection offered by these cells remains unclear. Here, we show that in vivo depletion of CX₃CR1⁺ mononuclear phagocytes (MNPs) resulted in more severe colitis and death after infection with Citrobacter rodentium. This phenotype was rescued by exogenous IL-22, which was endogenously produced by ILC3 in close spatial proximity to CX₃CR1⁺ MNPs that were dependent on MyD88 signaling. CX₃CR1⁺MNPs from both mouse and human tissue produced more IL-23 and IL-1β than conventional CD103(+) dendritic cells (cDCs) and were more efficient than cDCs in supporting IL-22 production in ILC3 in vitro and in vivo. Further, colonic ILC3 from patients with mild to moderate ulcerative colitis or Crohn's disease had increased IL-22 production. IBD-associated SNP gene set analysis revealed enrichment for genes selectively expressed in human intestinal MNPs. The product of one of these, TL1A, potently enhanced IL-23- and IL-1β-induced production of IL-22 and GM-CSF by ILC3. Collectively, these results reveal a critical role for CX₃CR1⁺ mononuclear phagocytes in integrating microbial signals to regulate colonic ILC3 function in IBD.

Alternate JournalJ. Exp. Med.
PubMed ID25024136
PubMed Central IDPMC4113938
Grant ListK08 DK099381 / DK / NIDDK NIH HHS / United States
K08 DK099381 / DK / NIDDK NIH HHS / United States
K99 DK091508 / DK / NIDDK NIH HHS / United States
K99DK091508 / DK / NIDDK NIH HHS / United States
R00 DK091508 / DK / NIDDK NIH HHS / United States
T32 CA009161 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States