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

• DOI: 10.1073/pnas.1808426115
• Publication Date: 2018-07-30T19:10:00Z
• 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
• Keywords: 0301 basic medicine; Macrophages; Dextran Sulfate; Toll-Like Receptors; CX3C Chemokine Receptor 1; Transcription Factor RelA; Heme; Biological Sciences; Colitis; 3. Good health; DNA-Binding Proteins; Intestines; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Animals; Cytokines; Iron, Dietary

Significance

Following hemorrhage in damaged tissues, hemoglobin induces macrophages (Mϕs) possessing ability to protect against tissue inflammation. Hemorrhage-appearing mucosa is observed in patients with inflammatory bowel disease. However, heme-mediated modulation of intestinal Mϕ activity remains poorly understood. Here, we provide evidence that Spi-C induced by heme is a key molecule for providing noninflammatory gene expression patterns of intestinal CX 3 CR1 high Mϕs. We found that the Spic deficiency in intestinal Mϕs resulted in increased sensitivity to dextran sodium sulfate-induced colitis. Heme-mediated Spi-C inhibited a subset of LPS-induced genes such as Il6 and Il1a by intestinal CX 3 CR1 high Mϕs through inhibition of IRF5-NF-κB p65 complex formation. These results reveal a mechanism modulating the noninflammatory phenotype of intestinal Mϕs and may help identify targets for therapy of intestinal inflammation.