Macrophage Regnase-3 limits tissue inflammation and injury via alternative splicing of pre-mRNA

RNA-binding proteins regulate posttranscriptional gene translation regulate but little is known about the cell type-specific functions of Regnase3. Here, we characterized the role of Regnase3 in macrophages using RankCre-Regnase3fl/fl mice. Single cell RNA sequencing demonstrated abundant Rank expression in kidney macrophages and a correlation with the induction of chemokines, macrophage phagocytosis and maturation upon kidney injury. In various kidney injury models, RankCre-Regnase3fl/fl mice showed more inflammatory macrophages, more kidney inflammation and injury, characterized by an increase in CCR2 positive leukocyte infiltration. Mechanistic in vitro studies revealed that Regnase3 suppresses macrophage polarization towards a pro-inflammatory phenotype modulates macrophage survival, migration and phagocytosis. In silico analysis suggests that Regnase-3 regulates the alternative splicing of inflammation-related pre-mRNAs such as pro-inflammatory cytokines/chemokines and chemokine receptors. Thus, macrophage Regnase-3 limits tissue inflammation and injury via alternative splicing of pro-inflammatory pre-mRNAs.