Abstract
Background & AimsInnate lymphoid cells (ILCs) are a heterogeneous group of mucosal inflammatory cells that participate in chronic intestinal inflammation. We investigated the role of interleukin 6 (IL6) in inducing activation of ILCs in mice and in human beings with chronic intestinal inflammation.MethodsILCs were isolated from colons of Tbx21-/- × Rag2-/- mice (TRUC), which develop colitis; patients with inflammatory bowel disease (IBD); and patients without colon inflammation (controls). ILCs were characterized by flow cytometry; cytokine production was measured by enzyme-linked immunosorbent assay and cytokine bead arrays. Mice were given intraperitoneal injections of depleting (CD4, CD90), neutralizing (IL6), or control antibodies. Isolated colon tissues were analyzed by histology, explant organ culture, and cell culture. Bacterial DNA was extracted from mouse fecal samples to assess the intestinal microbiota.ResultsIL17A- and IL22-producing, natural cytotoxicity receptor–negative, ILC3 were the major subset of ILCs detected in colons of TRUC mice. Combinations of IL23 and IL1α induced production of cytokines by these cells, which increased further after administration of IL6. Antibodies against IL6 reduced colitis in TRUC mice without significantly affecting the structure of their intestinal microbiota. Addition of IL6 increased production of IL17A, IL22, and interferon-γ by human intestinal CD3-negative, IL7-receptor–positive cells, in a dose-dependent manner.ConclusionsIL6 contributes to activation of colonic natural cytotoxicity receptor–negative, CD4-negative, ILC3s in mice with chronic intestinal inflammation (TRUC mice) by increasing IL23- and IL1α-induced production of IL17A and IL22. This pathway might be targeted to treat patients with IBD because IL6, which is highly produced in colonic tissue by some IBD patients, also increased the production of IL17A, IL22, and interferon-γ by cultured human colon CD3-negative, IL7-receptor–positive cells.
Highlights
BACKGROUND & AIMSInnate lymphoid cells (ILCs) are a heterogeneous group of mucosal inflammatory cells that participate in chronic intestinal inflammation
We validated the phenotype of ILCs in Tbx21-/- Rag2-/- ulcerative colitis (TRUC) mice, confirming excessive accumulation of IL17A- and IL22producing CD90þ IL7Rþ natural cytotoxicity receptor (NCR)- ILC3 in diseased colons (Figure 1A and 1B, Supplementary Figure 1A–D)
CD4expressing NCR- ILC3s resembling lymphoid tissue inducer cells participate in mucosal immune responses in the gut,[5] we considered the possibility that CD4þ ILCs might be the NCR- ILC3 subset responsible for mediating chronic inflammation in TRUC mice
Summary
BACKGROUND & AIMSInnate lymphoid cells (ILCs) are a heterogeneous group of mucosal inflammatory cells that participate in chronic intestinal inflammation. We investigated the role of interleukin 6 (IL6) in inducing activation of ILCs in mice and in human beings with chronic intestinal inflammation. RESULTS: IL17A- and IL22producing, natural cytotoxicity receptor–negative, ILC3 were the major subset of ILCs detected in colons of TRUC mice. Addition of IL6 increased production of IL17A, IL22, and interferon-g by human intestinal CD3-negative, IL7receptor–positive cells, in a dose-dependent manner. CONCLUSIONS: IL6 contributes to activation of colonic natural cytotoxicity receptor–negative, CD4-negative, ILC3s in mice with chronic intestinal inflammation (TRUC mice) by increasing IL23- and IL1a-induced production of IL17A and IL22. This pathway might be targeted to treat patients with IBD because
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