GSE129325
Immune homeostasis and regulation of the Interferon pathway require myeloid-derived Regnase-3
The RNase Regnase-1 is a master RNA regulator in macrophages and T cells that degrades cellular and viral RNA upon NF-kB signaling. The roles of the other Regnase family-members remain largely unknown. Here, we analyze Regnase-3 deficient mice, which develop hypertrophic lymph nodes. We used various mice with immune cell specific deletions of Regnase-3 to demonstrate that Regnase-3 acts specifically within myeloid cells. Regnase-3 deficiency systemically increased interferon signaling, which increased the proportion of immature B and innate immune cells and suppressed follicles and germinal center formation. Expression analysis revealed that Regnase-3 and Regnase-1 share protein degradation pathways. Nevertheless, Regnase-3 expression is specifically high in macrophages and transcriptionally controlled by interferon signaling. Although direct targets in macrophages remain unknown, Regnase-3 can bind, degrade and regulate mRNAs, such Zc3h12a encoding Regnase-1, in vitro. These data indicate that Regnase-3, like Regnase-1, is an RNase and essential for immune homeostasis, but has diverged as a key regulator for the interferon pathway in macrophages. Overall design: Alveolar macrophages from Regnase-3+/+ and Regnase-3-/- mice were sequenced (n=3/3). B cells: Lymph nodes were dissected from Regnase-3+/+ and Regnase-3-/- mice and divided into normal sized and enlarged lymph nodes in each Regnase-3-/- mouse (n=3/3/3).