Abstract Aging is characterized by immunosenescence, a gradual decline in immune function in which macrophages play a pivotal role in driving age-related inflammatory. NUDT21 (CFIm25), a key regulator of alternative polyadenylation (APA), has been implicated in inflammatory and aging-related disorders. However, its role in modulating macrophage via APA during immunosenescence remains unknown. The aim of this study was to define the role of NUDT21-mediated APA in macrophage during aging. Our results revealed significant inflammation in aging lung, accompanied by a reduction in NUDT21 expression in macrophages specifically. Then, we generated the macrophage-specific Nudt21 knockout mice (Nudt21f/f LysmCre and Nudt21f/fCD68 rtTA/tetOCre), and subjected them to the D-galactose induced aging model. Deletion of Nudt21 in macrophages enhanced the expression of senescence-associated secretory phenotype (SASP) factors, exacerbated the pro-inflammatory pulmonary microenvironment and aggravated lung aging in vivo. Mechanistically, NUDT21 deficiency drove macrophage polarization toward a pro-inflammatory M1 phenotype. Moreover, RNA-seq analysis of NUDT21-depleted bone marrow-derived macrophages (BMMs) revealed 3’ UTR shortening in phagocytosis-related transcripts, accompanied by impaired phagocytic function in vitro. Together, our findings underscore NUDT21 as a critical post-transcriptional RNA processor that regulates macrophage plasticity involved in the aging process, providing new insights into the pathogenesis of age-related diseases and potential therapeutic avenues. This abstract is funded by: NIH National Institute on Aging grant to T.M. (1R56AG076144-01A1), NIH National Heart, Lung, and Blood Institute grant to T.M. (1R01HL168128).
Wang et al. (Fri,) studied this question.