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

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 bowe...

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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS 2018-08, Vol.115 (33), p.8418-8423
Hauptverfasser: Kayama, Hisako, Kohyama, Masako, Okuzaki, Daisuke, Motooka, Daisuke, Barman, Soumik, Okumura, Ryu, Muneta, Masato, Hoshino, Katsuaki, Sasaki, Izumi, Ise, Wataru, Matsuno, Hiroshi, Nishimura, Junichi, Kurosaki, Tomohiro, Nakamura, Shota, Arase, Hisashi, Kaisho, Tsuneyasu, Takeda, Kiyoshi
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container_end_page 8423
container_issue 33
container_start_page 8418
container_title Proceedings of the National Academy of Sciences - PNAS
container_volume 115
creator Kayama, Hisako
Kohyama, Masako
Okuzaki, Daisuke
Motooka, Daisuke
Barman, Soumik
Okumura, Ryu
Muneta, Masato
Hoshino, Katsuaki
Sasaki, Izumi
Ise, Wataru
Matsuno, Hiroshi
Nishimura, Junichi
Kurosaki, Tomohiro
Nakamura, Shota
Arase, Hisashi
Kaisho, Tsuneyasu
Takeda, Kiyoshi
description 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 of Spi-C in intestinal CX₃CR1high Mϕs. Intestinal CX₃CR1high Mϕs 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 Mϕs to prevent colitis. LPS-induced production of IL-6 and IL-1α, but not IL-10 and TNF-α, by large intestinal Mϕs from Lyz2-cre; Spicflox/flox mice was markedly enhanced. The interaction of Spi-C with IRF5 was linked to disruption of the IRF5-NF-κB p65 complex formation, thereby abrogating recruitment of IRF5 and NF-κB p65 to the Il6 and Il1a promoters. Collectively, these results demonstrate that heme-mediated Spi-C is a key molecule for the non-inflammatory signature of intestinal Mϕs by suppressing the induction of a subset of TLR-inducible genes through binding to IRF5.
doi_str_mv 10.1073/pnas.1808426115
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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 of Spi-C in intestinal CX₃CR1high Mϕs. Intestinal CX₃CR1high Mϕs 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 Mϕs to prevent colitis. LPS-induced production of IL-6 and IL-1α, but not IL-10 and TNF-α, by large intestinal Mϕs from Lyz2-cre; Spicflox/flox mice was markedly enhanced. The interaction of Spi-C with IRF5 was linked to disruption of the IRF5-NF-κB p65 complex formation, thereby abrogating recruitment of IRF5 and NF-κB p65 to the Il6 and Il1a promoters. 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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 of Spi-C in intestinal CX₃CR1high Mϕs. Intestinal CX₃CR1high Mϕs 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 Mϕs to prevent colitis. LPS-induced production of IL-6 and IL-1α, but not IL-10 and TNF-α, by large intestinal Mϕs from Lyz2-cre; Spicflox/flox mice was markedly enhanced. The interaction of Spi-C with IRF5 was linked to disruption of the IRF5-NF-κB p65 complex formation, thereby abrogating recruitment of IRF5 and NF-κB p65 to the Il6 and Il1a promoters. 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subjects Animals
Biological Sciences
Bleeding
Colitis
Colitis - drug therapy
Complex formation
CX3C Chemokine Receptor 1 - physiology
Cytokines - biosynthesis
Dextran
Dextran Sulfate - toxicity
DNA-Binding Proteins - physiology
Flox
Gene expression
Genes
Helper cells
Heme
Heme - pharmacology
Hemoglobin
Hemorrhage
Homeostasis
Immune system
Inflammation
Inflammatory bowel disease
Inflammatory bowel diseases
Interleukin 1
Interleukin 10
Interleukin 6
Intestine
Intestines - immunology
Iron, Dietary - administration & dosage
Lipopolysaccharides
Lymphocytes T
Macrophages
Macrophages - immunology
Mice
Mice, Inbred C57BL
Mucosa
NF-κB protein
Pathogens
Proteins
Sodium
Sodium sulfate
Sulfates
Toll-like receptors
Toll-Like Receptors - physiology
Transcription Factor RelA - physiology
Tumor necrosis factor-α
title Heme ameliorates dextran sodium sulfate-induced colitis through providing intestinal macrophages with noninflammatory profiles
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