title: Cross-talk between RORγt+ innate lymphoid cells and intestinal macrophages induces mucosal IL-22 production in Crohn's disease.
abstract: BACKGROUND
  Interleukin (IL)-22-producing RORγt innate lymphoid cells (ILCs) play a pivotal role in intestinal immunity. Recent reports demonstrated that ILCs contribute to mucosal protection and intestinal inflammation in mice. In humans, numbers of RORγt ILCs are significantly increased in the intestine of patients with Crohn's disease (CD), suggesting that ILCs may be associated with intestinal inflammation in CD. However, the mechanism by which ILCs are regulated in the intestine of patients with CD is poorly understood. This study aimed to determine the activation mechanism of intestinal ILCs in patients with CD.
  
  
  METHODS
  CD45 lineage marker ILCs were isolated from intestinal lamina propria of patients with CD. ILCs were then subdivided into 4 distinct populations based on the expression of CD56 and CD127. Purified ILC subsets were cocultured with intestinal CD14 macrophages, and IL-22 production was evaluated.
  
  
  RESULTS
  CD127CD56 and CD127CD56 ILC, but not CD127CD56 or CD127CD56 ILC, subsets expressed RORγt and produced IL-22. IL-22 production by these ILC subsets was enhanced when ILCs were cocultured with intestinal macrophages. IL-23 or cell-to-cell contact was required for macrophage-mediated activation of ILCs. IL-22 production by ILCs was perturbed in inflamed mucosa compared with noninflamed mucosa. IL-22 induced the expression of Reg1α and Claudin-1 in human intestinal epithelial organoids.
  
  
  CONCLUSIONS
  RORγt ILCs might enhance mucosal barrier function through the upregulation of Reg1α through production of IL-22. Although CD14 macrophages augment intestinal inflammation in patients with CD, macrophages also promote a negative feedback pathway through the activation of IL-22 production by RORγt ILCs.
authors.affiliation: *Department of Gastroenterology and Hepatology, and †Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan; ‡Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan; §Life Science of Medical Bio Science, Waseda University School of Advanced Science and Engineering, Tokyo, Japan; ‖Department of Surgery, Yokohama Municipal Citizen's Hospital, Yokohama, Japan; and ¶Coloproctology Center of Social Health Insurance Medical Center, Tokyo, Japan.
authors.forename: Shinta
authors.initials: S
authors.lastname: Mizuno
authors.forename: Yohei
authors.initials: Y
authors.lastname: Mikami
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Kamada
authors.forename: Tango
authors.initials: T
authors.lastname: Handa
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hayashi
authors.forename: Toshiro
authors.initials: T
authors.lastname: Sato
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Matsuoka
authors.forename: Mami
authors.initials: M
authors.lastname: Matano
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ohta
authors.forename: Akira
authors.initials: A
authors.lastname: Sugita
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Koganei
authors.forename: Rikisaburo
authors.initials: R
authors.lastname: Sahara
authors.forename: Masakazu
authors.initials: M
authors.lastname: Takazoe
authors.forename: Tadakazu
authors.initials: T
authors.lastname: Hisamatsu
authors.forename: Takanori
authors.initials: T
authors.lastname: Kanai
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016022:Case-Control Studies; D002478:Cells, Cultured; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053759:Interleukin-23 / Q000235:genetics / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism*; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000097043:Interleukin-22
chemical_list: D053759:Interleukin-23; D007378:Interleukins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D012333:RNA, Messenger; D000097043:Interleukin-22