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Gamm, Matthias von; Schaub, Annalisa; Jones, Alisha N.; Wolf, Christine; Behrens, Gesine; Lichti, Johannes; Essig, Katharina; Macht, Anna; Pircher, Joachim; Ehrlich, Andreas; Davari, Kathrin; Chauhan, Dhruv; Busch, Benjamin; Wurst, Wolfgang; Feederle, Regina; Feuchtinger, Annette; Tschoep, Matthias H.; Friedel, Caroline C.; Hauck, Stefanie M.; Sattler, Michael; Geerlof, Arie; Hornung, Veit; Heissmeyer, Vigo; Schulz, Christian; Heikenwalder, Mathias; Glasmacher, Elke (2019): Immune homeostasis and regulation of the interferon pathway require myeloid-derived Regnase-3. In: Journal of Experimental Medicine, Vol. 216, No. 7: pp. 1700-1723
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Abstract

The RNase Regnase-1 is a master RNA regulator in macrophages and T cells that degrades cellular and viral RNA upon NF-kappa B 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.