Proc. Natl. Acad. Sci. USA https://doi.org/10.1073/pnas.1808426115 (2018)

Hemorrhage releases hemoglobin, which initiates a wound-healing response by macrophages. In the Proceedings of the National Academy of Sciences, Takeda and colleagues show that heme induces expression of Spi-C in CX3CR1hi intestinal macrophages. In turn, Spi-C binds to IRF5 and interferes with its ability to drive the expression of select genes encoding pro-inflammatory cytokines, such as Il1a and Il6. Conditional knockout of Spi-C in macrophages exacerbates experimental colitis, whereas peritoneal delivery of heme ameliorates signs of this disease in a Spi-C-dependent manner. These findings mechanistically link tissue injury in the gut to a macrophage-driven restitutive response.