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

Randy S. Longman, Gretchen E. Diehl, Daniel A. Victorio, Jun R. Huh, Carolina Galan, Emily R. Miraldi, Arun Swaminath, Richard Bonneau, Ellen J. Scherl, Dan R. Littman

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1571-1583
Number of pages13
JournalJournal of Experimental Medicine
Volume211
Issue number8
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Longman, R. S., Diehl, G. E., Victorio, D. A., Huh, J. R., Galan, C., Miraldi, E. R., Swaminath, A., Bonneau, R., Scherl, E. J., & Littman, D. R. (2014). CX3CR1+ mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22. Journal of Experimental Medicine, 211(8), 1571-1583. https://doi.org/10.1084/jem.20140678