Macrophage SELENOP controls neutrophil homeostasis through redox stress regulation in Crohn's disease.

BACKGROUND: Neutrophil accumulation and oxidative injury are prominent features of Crohn's disease (CD). This study aimed to investigate whether macrophage-derived SELENOP functions as a redox checkpoint in macrophage-neutrophil crosstalk during CD. METHODS: Inflamed and non-inflamed colon tissues from CD patients were examined by single-cell RNA sequencing. SELENOP function was assessed in macrophages, macrophage-neutrophil co-cultures and inflammation models. Mechanistic studies included loss- and gain-of-function assays, co-immunoprecipitation, ubiquitination assays, and rescue experiments. In vivo validation was performed using myeloid-specific SELENOP-deficient mice with TNBS-induced colitis and SELENOP-overexpressing IL-10-deficient mice. RESULTS: SELENOP was selectively diminished in colon macrophages from inflamed CD lesions and its reduction was associated with more severe disease activity and postoperative recurrence. Functionally, SELENOP reduction in macrophages acquired a pro-oxidative and hyperinflammatory state through SESN2/NRF2 antioxidant signaling and CAP1. TRIP12 promoted ubiquitin-dependent SELENOP degradation, whereas CREB1 and SMARCA4 cooperatively activated SELENOP transcription. SELENOP-deficient macrophages altered redox and cADPR-associated metabolic signaling, thereby inducing neutrophil oxidative stress, apoptosis and NET formation. Myeloid SELENOP deletion aggravated experimental TNBS-induced colitis, while SELENOP overexpression alleviated IL-10-deficient colitis in a macrophage-dependent manner. CONCLUSIONS: Our findings identify macrophage-derived SELENOP as a redox checkpoint that restrains pathogenic macrophage-neutrophil communication in CD. Targeting the macrophage SELENOP may recalibrate oxidative stress-driven colonic inflammation.