Immune homeostasis and regulation of the interferon pathway require myeloid-derived Regnase-3

Abstract

The RNase Regnase-1 is a master RNA regulator in macrophages and T cells that degrades cellular and viral RNA upon NF-κB signaling. The roles of its family members, however, remain largely unknown. Here, we analyzed <i>Regnase-3</i>-deficient mice, which develop hypertrophic lymph nodes. We used various mice with immune cell-specific deletions of <i>Regnase-3</i> to demonstrate that Regnase-3 acts specifically within myeloid cells. <i>Regnase-3</i> deficiency systemically increased IFN signaling, which increased the proportion of immature B and innate immune cells, and suppressed follicle and germinal center formation. Expression analysis revealed that Regnase-3 and Regnase-1 share protein degradation pathways. Unlike Regnase-1, Regnase-3 expression is high specifically in macrophages and is transcriptionally controlled by IFN signaling. Although direct targets in macrophages remain unknown, Regnase-3 can bind, degrade, and regulate mRNAs, such as <i>Zc3h12a</i> (<i>Regnase-1</i>), in vitro. These data indicate that Regnase-3, like Regnase-1, is an RNase essential for immune homeostasis but has diverged as key regulator in the IFN pathway in macrophages.