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

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. 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. 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. 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.