NUDT21 Regulates Macrophage Cytokine Responses via Alternative Polyadenylation in ARDS

Acute respiratory distress syndrome (ARDS) is a life-threatening condition driven by uncontrolled inflammation and immune dysregulation. The post-transcriptional mechanisms that fine-tune macrophage activation in ARDS remain poorly understood. Here, we identify Nudix hydrolase 21 (NUDT21) as a critical regulator of macrophage-mediated inflammation through alternative polyadenylation (APA). NUDT21 was downregulated in macrophages from human and mouse ARDS lungs. Functional studies using macrophage-specific Nudt21 knockout mice (Nudt21^f/fLysmCre, Nudt21^f/fCxcr1Cre, or mice with bone marrow transplantation) revealed that Nudt21 loss amplifies cytokine production, neutrophil infiltration, and lung injury in lipopolysaccharide or bleomycin-induced lung injury models. Notably, neutrophil depletion did not alleviate the exaggerated inflammation in Nudt21^f/fLysmCre mice, confirming a macrophage-specific mechanism. In contrast, Nudt21^f/fCD68 rtTA/tetOCre mice did not exhibit increased injury, likely because alveolar macrophages-but not recruited macrophages-play a major role in the LPS model. Transcriptome profiling revealed widespread 3'UTR shortening of inflammatory genes and elevated protein expression in NUDT21-deficient macrophages, indicating APA-mediated translational activation. Furthermore, we identified hypoxia-induced microRNA-181a as an upstream repressor of NUDT21, linking oxygen stress to APA remodeling. Collectively, these findings uncover a previously unrecognized hypoxia-miR-181a-NUDT21-APA axis that amplifies macrophage inflammation and lung injury.