Macrophage Zc3h12c Limits Tissue Inflammation and Injury via Alternative Splicing of Pre-mRNA.

Abstract

RNA-binding proteins regulate post-transcriptional gene translation, but the macrophage-specific role of Zc3h12c remains poorly characterized. Here, the role of Zc3h12c in macrophages is characterized using Tnfrsf11a-Zc3h12cmice. Both Tnfrsf11a and Zc3h12c are highly expressed in the kidney tissue from patients with chronic kidney disease and showed a positive association with an interstitial fibrosis score. Single cell RNA sequencing demonstrated abundant Tnfrsf11a expression in murine kidney macrophages and a correlation with the induction of chemokines, macrophage phagocytosis, and activation upon kidney injury. In various kidney injury models, Tnfrsf11a-Zc3h12cmice suffered from more injury and inflammation in the kidney, characterized by an increase in Ccr2 positive leukocyte infiltration. Mechanistic in vitro studies revealed that Zc3h12c suppresses macrophage activation toward a pro-inflammatory phenotype, modulates macrophage survival, migration, and phagocytosis. Both in silico and in vitro analysis indicated that Zc3h12c regulates the pro-inflammatory cytokines/chemokines and chemokine receptors expression and modulates the alternative splicing of pre-mRNAs STAT1. Thus, macrophage-derived Zc3h12c limits tissue inflammation and injury, potentially via alternate splicing of pre-mRNAs.