Immune homeostasis and regulation of the interferon pathway require myeloid-derived Regnase-3.
J Exp Med. 2019 May 24. pii: jem.20181762. doi: 10.1084/jem.20181762. [Epub ahead of print]
|Authors/Editors:||von Gamm M, Schaub A, Jones AN, Wolf C, Behrens G, Lichti J, Essig K, Macht A, Pircher J, Ehrlich A, Davari K, Chauhan D, Busch B, Wurst W Feederle R Feuchtinger A, Tschöp MH, Friedel CC, Hauck SM, Sattler M, Geerlof A, Hornung V, Heissmeyer V, Schulz C, Heikenwalder M, Glasmacher E.|
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 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 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 Zc3h12a (Regnase-1), 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.