Developmentally endothelial locus-1 facilitates intestinal inflammation resolution by suppressing the Cmpk2-cGAS-STING pathway and promoting reparatory macrophage transition

DEL-1 attenuates intestinal inflammation and promotes inflammation resolution through several mechanisms: DEL-1 inhibits the Cmpk2-dependent mtDNA synthesis and consequently cGAS-STING signaling activation. DEL-1 also promotes reparative macrophage transition. Furthermore, the regulatory effect of DEL-1 is mediated through promoting the ubiquitin–proteasome-dependent degradation of transcription factor Spi1, and affecting its transcriptional regulatory capacity of Cmpk2 and Il10. In parallel, DEL-1 inhibits neutrophil recruitment, repairs the intestinal barrier, and improves intestinal microbiota dysbiosis to promote intestinal inflammation resolution. • DEL-1 was downregulated in IBD patients, and resurged as inflammation resolution. • DEL-1 plays a dual role of anti-inflammatory and pro-resolution in IBD. • DEL-1 suppresses Cmpk2-cGAS-STING pathway to alleviate intestinal inflammation. • DEL-1 promotes reparative macrophage transition in the repair model of colitis. • DEL-1 regulates transcription of Cmpk2 and Il10 by promoting Spi1 degradation. Abnormalities in inflammation resolution function are intimately linked to chronic inflammation, and proresolution therapies may offer novel opportunities for IBD treatment. Developmental endothelial locus 1 (DEL-1), a natural modulator of tissue immunity and inflammation resolution, has not been studied in IBD. We aimed to investigate the expression and functions of DEL-1 in IBD. Assessment of DEL-1 expression in patients, murine models, and cellular levels. To explore the effects of DEL-1 in the acute and recovery phases of inflammation, overexpression plasmids, adeno-associated viruses for DEL-1 knockdown, and DEL-1-Fc fusion proteins were administered to cells and mice. Additionally, the potential mechanism of DEL-1 in IBD was demonstrated using flow cytometry, RNA-Seq, ChIP, dual-luciferase reporter assays and 16S rRNA. DEL-1 levels were significantly reduced in IBD patients, colitis mice and macrophages, while the levels increased with inflammation to resolve. Transfection with DEL-1 overexpression plasmid or DEL-1-Fc intervention reduces levels of inflammatory cytokines in both phases and upregulates reparative gene levels in the recovery phase. DEL-1 knockdown inhibits inflammation resolution of colitis. Mechanistically, we demonstrated that DEL-1 inhibits Cmpk2-dependent mtDNA synthesis, thereby inhibiting the cGAS-STING pathway to ameliorate intestinal inflammation. Moreover, DEL-1 promotes reparative macrophage transition in the repair model of colitis. Spi1 was identified as a transcription factor that regulates Cmpk2 and the reparative gene Il10. Intervention with overexpression plasmid of Spi1 or Cmpk2 or the STING agonist DMXAA reverses the effects of DEL-1. In parallel, DEL-1 also inhibits neutrophil recruitment, repairs the intestinal barrier, and improves intestinal microbiota dysbiosis. We report the first demonstration that DEL-1 significantly ameliorates colonic inflammation in colitis mice. Our findings elucidate a novel mechanism wherein DEL-1 exerts its protective effects by suppressing the Cmpk2-cGAS-STING pathway and promoting reparative macrophage transition. These results collectively position DEL-1 as a promising therapeutic avenue for IBD.