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

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 phago...

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Bibliographic Details
Published in:	The Journal of experimental medicine Vol. 211; no. 8; pp. 1571 - 1583
Main Authors:	Longman, Randy S, Diehl, Gretchen E, Victorio, Daniel A, Huh, Jun R, Galan, Carolina, Miraldi, Emily R, Swaminath, Arun, Bonneau, Richard, Scherl, Ellen J, Littman, Dan R
Format:	Journal Article
Language:	English
Published:	United States The Rockefeller University Press 28-07-2014
Subjects:	Animals Citrobacter rodentium - drug effects Citrobacter rodentium - physiology Colitis - immunology Colitis - microbiology Colitis - pathology Colitis - prevention & control CX3C Chemokine Receptor 1 Dendrites - drug effects Dendrites - metabolism Feces Humans Immunity, Innate - drug effects Interleukin-1beta - pharmacology Interleukin-22 Interleukin-23 - metabolism Interleukins - biosynthesis Intestinal Mucosa - drug effects Intestinal Mucosa - pathology Lymphocytes - drug effects Lymphocytes - metabolism Lymphocytes - microbiology Mice Monocytes - drug effects Monocytes - metabolism Phagocytes - drug effects Phagocytes - metabolism Phagocytes - microbiology Receptors, Chemokine - metabolism Toll-Like Receptors - metabolism Tumor Necrosis Factor Ligand Superfamily Member 15 - metabolism
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 R.S. Longman and G.E. Diehl contributed equally to this paper. J.R. Huh’s present address is University of Massachusetts Medical School, Worcester, MA 01605. A. Swaminath’s present address is Lennox Hill Hospital, New York, NY 10075.
ISSN:	0022-1007 1540-9538
DOI:	10.1084/jem.20140678