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Heme ameliorates dextran sodium sulfate-induced colitis through providing intestinal macrophages with noninflammatory profiles.

ABSTRACT: The local environment is crucial for shaping the identities of tissue-resident macrophages (M?s). When hemorrhage occurs in damaged tissues, hemoglobin induces differentiation of anti-inflammatory M?s with reparative function. Mucosal bleeding is one of the pathological features of inflammatory bowel diseases. However, the heme-mediated mechanism modulating activation of intestinal innate immune cells remains poorly understood. Here, we show that heme regulates gut homeostasis through induction of Spi-C in intestinal CX3CR1high M?s. Intestinal CX3CR1high M?s highly expressed Spi-C in a heme-dependent manner, and myeloid lineage-specific Spic-deficient (Lyz2-cre; Spicflox/flox ) mice showed severe intestinal inflammation with an increased number of Th17 cells during dextran sodium sulfate-induced colitis. Spi-C down-regulated the expression of a subset of Toll-like receptor (TLR)-inducible genes in intestinal CX3CR1high M?s to prevent colitis. LPS-induced production of IL-6 and IL-1?, but not IL-10 and TNF-?, by large intestinal M?s from Lyz2-cre; Spicflox/flox mice was markedly enhanced. The interaction of Spi-C with IRF5 was linked to disruption of the IRF5-NF-?B p65 complex formation, thereby abrogating recruitment of IRF5 and NF-?B p65 to the Il6 and Il1a promoters. Collectively, these results demonstrate that heme-mediated Spi-C is a key molecule for the noninflammatory signature of intestinal M?s by suppressing the induction of a subset of TLR-inducible genes through binding to IRF5.

SUBMITTER: Kayama H

PROVIDER: S-EPMC6099887 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Heme ameliorates dextran sodium sulfate-induced colitis through providing intestinal macrophages with noninflammatory profiles.

Kayama Hisako H Kohyama Masako M Okuzaki Daisuke D Motooka Daisuke D Barman Soumik S Okumura Ryu R Muneta Masato M Hoshino Katsuaki K Sasaki Izumi I Ise Wataru W Matsuno Hiroshi H Nishimura Junichi J Kurosaki Tomohiro T Nakamura Shota S Arase Hisashi H Kaisho Tsuneyasu T Takeda Kiyoshi K

Proceedings of the National Academy of Sciences of the United States of America 20180730 33

The local environment is crucial for shaping the identities of tissue-resident macrophages (Mϕs). When hemorrhage occurs in damaged tissues, hemoglobin induces differentiation of anti-inflammatory Mϕs with reparative function. Mucosal bleeding is one of the pathological features of inflammatory bowel diseases. However, the heme-mediated mechanism modulating activation of intestinal innate immune cells remains poorly understood. Here, we show that heme regulates gut homeostasis through induction ...[more]

PMID: 30061415

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Project description:Alterations in the intestinal lymphatic network are pathological processes as related to inflammatory bowel disease (IBD). In this study, we demonstrated that reduction in inflammation-induced lymphangiogenesis ameliorates experimental acute colitis. A soluble and stable angiopoietin-1 (Ang1) variant, COMP-Ang1, possesses anti-inflammatory and angiogenic effects. We investigated the effects of COMP-Ang1 on an experimental colonic inflammation model. Experimental colitis was induced in mice by administering 3% dextran sulfate sodium (DSS) via drinking water. We determined body weight, disease activity indices, histopathological scores, lymphatic density, anti-ER-HR3 staining, and the expression of members of the vascular endothelial growth factor (VEGF) family and various inflammatory cytokines in the mice. The density of lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) and VEGFR-3-positive lymphatic vessels increased in mice with DSS-induced colitis. We observed that COMP-Ang1-treated mice showed less weight loss, fewer clinical signs of colitis, and longer colons than Ade-DSS-treated mice. COMP-Ang1 also significantly reduced the density of LYVE-1-positive lymphatic vessels and the disruption of colonic architecture that is normally associated with colitis and repressed the immunoregulatory response. Further, COMP-Ang1 treatment reduced both M1 and M2 macrophage infiltration into the inflamed colon, which involved inhibition of VEGF-C and D expression. Thus, COMP-Ang1, which acts by reducing inflammation-induced lymphangiogenesis, may be used as a novel therapeutic for the treatment of IBD and other inflammatory diseases.Key messagesCOMP-Ang1 decreases inflammatory-induced lymphangiogenesis in experimental acute colitis. COMP-Ang1 improves the symptom of DSS-induced inflammatory response. COMP-Ang1 reduces the expression of pro-inflammatory cytokines in inflamed colon. COMP-Ang1 reduces the expression of VEGFs in inflamed colon. COMP-Ang1 prevents infiltration of macrophages in a DSS-induced colitis model.

Dataset Information

Heme ameliorates dextran sodium sulfate-induced colitis through providing intestinal macrophages with noninflammatory profiles.

Publications

Heme ameliorates dextran sodium sulfate-induced colitis through providing intestinal macrophages with noninflammatory profiles.

Similar Datasets

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