Heme ameliorates the colitis through providing intestinal macrophages
with non-inflammatory profiles
Abstract
The local environment is crucial for shaping the identities of tissue-resident Ms. When hemorrhage occurs indamaged 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. Hisakao Kayama, Masako
Kohyama, and Kiyoshi Takeda group show that heme regulates gut homeostasis through induction of Spi-C inintestinal CX3CR1high Ms. Intestinal CX3CR1high Ms highly expressed Spi-C in a heme-dependent manner, andmyeloid lineage-specific Spic deficient (Lyz2-cre; Spicflox/flox) mice showed severe intestinal inflammation withincreased number of Th17 cells during dextran sodium sulfate-induced colitis. Spi-C downregulated the expressionof a subset of 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 IRF5-NF-B p65 complex formation, thereby
abrogating recruitment of IRF5 and NF-B p65 to the Il6 and Il1a promoters. Collectively, these results demonstratethat heme-mediated Spi-C is a key molecule for the non-inflammatory signature of intestinal Ms by suppressing theinduction of a subset of TLR-inducible genes through binding to IRF5.

Mechanism of the regulation for the intestinal macrophages.
The heme-induced transcription factor Spi-C inhibits the dimer formation of transcription factors
IRF5 and NF-κB p65. As a result, the expression of some TLR4-dependent genes is suppressed.

1 Significance
Following hemorrhage in damaged tissues, hemoglobin induces Ms possessing the ability to protect against tissue
inflammation. Hemorrhage-appearing mucosa is observed in patients with IBD. However, heme-mediatedmodulation of intestinal M activity remains poorly understood. Here, we provide evidence that Spi-C induced byheme is a key molecule for providing non-inflammatory gene expression patterns of intestinal CX3CR1high Ms.
We found that the Spic deficiency in intestinal Ms resulted in increased sensitivity to DSS-induced colitis. Hememediated Spi-C inhibited a subset of LPS-induced gene such as Il6 and Il1a by intestinal CX3CR1high Ms throughinhibition of IRF5-NF-B p65 complex formation. These results reveal a novel mechanism modulating noninflammatory phenotype of intestinal Ms and may help identify new targets for therapy of intestinal inflammation.

 Article
Journal: Proceedings of the National Academy of Sciences of the United States of America (PNAS)
July 31, 2018 online
Title: “Heme ameliorates dextran sodium sulfate-induced colitis through providing intestinal macrophages with
non-inflammatory profiles”
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*, and Kiyoshi Takeda*.
(＃equally contributed, *Corresponding authors）

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