title: CX₃CR1⁺ mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22.
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.
authors.affiliation: The Kimmel Center for Biology and Medicine of the Skirball Institute and Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016 The Jill Roberts Center for IBD, Department of Medicine, Weill-Cornell Medical College, New York, NY 10021 ral2006@med.cornell.edu dan.littman@med.nyu.edu.
authors.forename: Randy S
authors.initials: RS
authors.lastname: Longman
authors.affiliation: The Kimmel Center for Biology and Medicine of the Skirball Institute and Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016.
authors.forename: Gretchen E
authors.initials: GE
authors.lastname: Diehl
authors.affiliation: The Kimmel Center for Biology and Medicine of the Skirball Institute and Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016 The Jill Roberts Center for IBD, Department of Medicine, Weill-Cornell Medical College, New York, NY 10021.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Victorio
authors.affiliation: The Kimmel Center for Biology and Medicine of the Skirball Institute and Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016.
authors.forename: Jun R
authors.initials: JR
authors.lastname: Huh
authors.affiliation: The Kimmel Center for Biology and Medicine of the Skirball Institute and Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016.
authors.forename: Carolina
authors.initials: C
authors.lastname: Galan
authors.affiliation: The Kimmel Center for Biology and Medicine of the Skirball Institute and Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016 Center for Genomics and Systems Biology, Department of Biology; and Courant Institute of Mathematical Sciences, Computer Science Department, New York University, New York, NY10003 Center for Genomics and Systems Biology, Department of Biology; and Courant Institute of Mathematical Sciences, Computer Science Department, New York University, New York, NY10003.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Miraldi
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY 10032.
authors.forename: Arun
authors.initials: A
authors.lastname: Swaminath
authors.affiliation: Center for Genomics and Systems Biology, Department of Biology; and Courant Institute of Mathematical Sciences, Computer Science Department, New York University, New York, NY10003 Center for Genomics and Systems Biology, Department of Biology; and Courant Institute of Mathematical Sciences, Computer Science Department, New York University, New York, NY10003.
authors.forename: Richard
authors.initials: R
authors.lastname: Bonneau
authors.affiliation: The Jill Roberts Center for IBD, Department of Medicine, Weill-Cornell Medical College, New York, NY 10021 Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY 10032.
authors.forename: Ellen J
authors.initials: EJ
authors.lastname: Scherl
authors.affiliation: The Kimmel Center for Biology and Medicine of the Skirball Institute and Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016The Kimmel Center for Biology and Medicine of the Skirball Institute and Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016 ral2006@med.cornell.edu dan.littman@med.nyu.edu.
authors.forename: Dan R
authors.initials: DR
authors.lastname: Littman
mesh_terms: D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D044082:Citrobacter rodentium / Q000187:drug effects / Q000502:physiology; D003092:Colitis / Q000276:immunology* / Q000382:microbiology / Q000473:pathology* / Q000517:prevention & control; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism; D005243:Feces; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D053583:Interleukin-1beta / Q000494:pharmacology; D053759:Interleukin-23 / Q000378:metabolism; D007378:Interleukins / Q000096:biosynthesis*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D010586:Phagocytes / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology; D019707:Receptors, Chemokine / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000378:metabolism; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000378:metabolism; D000097043:Interleukin-22
chemical_list: D000073883:CX3C Chemokine Receptor 1; D053583:Interleukin-1beta; D053759:Interleukin-23; D007378:Interleukins; D019707:Receptors, Chemokine; D051193:Toll-Like Receptors; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D000097043:Interleukin-22; C095235:CX3CR1 protein, human; C471885:Cx3cr1 protein, mouse; C117026:TNFSF15 protein, human