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

Abstract

INTRODUCTION: 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. OBJECTIVES: We aimed to investigate the expression and functions of DEL-1 in IBD. METHODS: 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. RESULTS: 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. CONCLUSION: 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.