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 (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 noninflammatory signature of intestinal Mϕs by suppressing the induction of a subset of TLR-inducible genes through binding to IRF5.

• Authors: Hisako Kayama, Masako Kohyama, Daisuke Okuzaki, Daisuke Motooka, Soumik Barman, Ryu Okumura, Masato Muneta, Katsuaki Hoshino, Izumi Sasaki, Wataru Ise, Hiroshi Matsuno, Junichi Nishimura, Tomohiro Kurosaki, Shota Nakamura, Hisashi Arase, Tsuneyasu Kaisho, Kiyoshi Takeda
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 115 Issue 33 Pg. 8418-8423 (08 14 2018) ISSN: 1091-6490 [Electronic] United States
• PMID: 30061415 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 the Author(s). Published by PNAS.

Chemical References

• CX3C Chemokine Receptor 1
• Cx3cr1 protein, mouse
• Cytokines
• DNA-Binding Proteins
• Iron, Dietary
• Spic protein, mouse
• Toll-Like Receptors
• Transcription Factor RelA
• Heme
• Dextran Sulfate

Topics

• Animals
• CX3C Chemokine Receptor 1 (physiology)
• Colitis (drug therapy)
• Cytokines (biosynthesis)
• DNA-Binding Proteins (physiology)
• Dextran Sulfate (toxicity)
• Heme (pharmacology)
• Intestines (immunology)
• Iron, Dietary (administration & dosage)
• Macrophages (immunology)
• Mice
• Mice, Inbred C57BL
• Toll-Like Receptors (physiology)
• Transcription Factor RelA (physiology)