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Cross-talk Between RORγt+ Innate Lymphoid Cells and Intestinal Macrophages Induces Mucosal IL-22 Production in Crohn's Disease

Mizuno, Shinta MD, PhD*; Mikami, Yohei MD, PhD*,†; Kamada, Nobuhiko PhD; Handa, Tango MPharm*; Hayashi, Atsushi MPharm*; Sato, Toshiro MD, PhD*; Matsuoka, Katsuyoshi MD, PhD*; Matano, Mami MAgr*; Ohta, Yuki BSc§; Sugita, Akira MD; Koganei, Kazutaka MD; Sahara, Rikisaburo MD; Takazoe, Masakazu MD; Hisamatsu, Tadakazu MD, PhD*; Kanai, Takanori MD, PhD*

doi: 10.1097/MIB.0000000000000105
Original Basic Research Articles

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: CD127+CD56 and CD127+CD56+ 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.

Article first published online 2 July 2014.Supplemental Digital Content is Available in the Text.

*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.

Reprints: Takanori Kanai, MD, PhD, Department of Gastroenterology and Hepatology, Keio University School of Medicine, 35, Shonanomachi, Shinjuku, Tokyo 160-8582, Japan (e-mail:

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (

Supported in part by grants-in-aid for Scientific Research, Scientific Research on Priority Areas, Exploratory Research and Creative Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology (T.K.); Japan Foundation for Applied Enzymology (S.M.); Keio University Grant-in-Aid for Encouragement of Young Medical Scientists (S.M.), Grants-in-Aid for JSPS Fellows (Y.M.), Crohn's and Colitis Foundation of America (N.K.); and the University of Michigan Gastrointestinal Peptide Research Center Grant 5 P30 DK034933 (N.K.).

The authors have no conflicts of interest to disclose.

Received March 27, 2014

Accepted May 07, 2014

© Crohn's & Colitis Foundation of America, Inc.
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