| First Author | Kayama H | Year | 2018 |
| Journal | Proc Natl Acad Sci U S A | Volume | 115 |
| Issue | 33 | Pages | 8418-8423 |
| PubMed ID | 30061415 | Mgi Jnum | J:265082 |
| Mgi Id | MGI:6195574 | Doi | 10.1073/pnas.1808426115 |
| Citation | Kayama H, et al. (2018) Heme ameliorates dextran sodium sulfate-induced colitis through providing intestinal macrophages with noninflammatory profiles. Proc Natl Acad Sci U S A 115(33):8418-8423 |
| abstractText | The local environment is crucial for shaping the identities of tissue-resident macrophages (Mvarphis). When hemorrhage occurs in damaged tissues, hemoglobin induces differentiation of anti-inflammatory Mvarphis 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 CX3CR1(high) Mvarphis. Intestinal CX3CR1(high) Mvarphis highly expressed Spi-C in a heme-dependent manner, and myeloid lineage-specific Spic-deficient (Lyz2-cre; Spic(flox/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 CX3CR1(high) Mvarphis to prevent colitis. LPS-induced production of IL-6 and IL-1alpha, but not IL-10 and TNF-alpha, by large intestinal Mvarphis from Lyz2-cre; Spic(flox/flox) mice was markedly enhanced. The interaction of Spi-C with IRF5 was linked to disruption of the IRF5-NF-kappaB p65 complex formation, thereby abrogating recruitment of IRF5 and NF-kappaB 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 Mvarphis by suppressing the induction of a subset of TLR-inducible genes through binding to IRF5. |
