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

被引:29
作者
von Gamm, Matthias [1 ]
Schaub, Annalisa [1 ,2 ]
Jones, Alisha N. [3 ,4 ]
Wolf, Christine [5 ]
Behrens, Gesine [6 ]
Lichti, Johannes [1 ]
Essig, Katharina [7 ]
Macht, Anna [1 ]
Pircher, Joachim [8 ]
Ehrlich, Andreas [8 ]
Davari, Kathrin [9 ]
Chauhan, Dhruv [10 ,11 ]
Busch, Benjamin [12 ]
Wurst, Wolfgang [13 ,14 ,15 ,16 ]
Feederle, Regina [17 ]
Feuchtinger, Annette [18 ]
Tschoep, Matthias H. [1 ,19 ]
Friedel, Caroline C. [20 ]
Hauck, Stefanie M. [21 ]
Sattler, Michael [3 ,4 ]
Geerlof, Arie [3 ]
Hornung, Veit [10 ,11 ]
Heissmeyer, Vigo [6 ,22 ]
Schulz, Christian [8 ,23 ]
Heikenwalder, Mathias [24 ]
Glasmacher, Elke [1 ,7 ]
机构
[1] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Diabet & Obes, Helmholtz Diabet Ctr, Neuherberg, Germany
[2] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Mol Toxicol & Pharmacol, Neuherberg, Germany
[3] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Struct Biol, Neuherberg, Germany
[4] Tech Univ Munich, Ctr Integrated Prot Sci Munich, Chem Dept, Garching, Germany
[5] Helmholtz Zentrum Munchen, Inst Environm Med, German Res Ctr Environm Hlth, Neuherberg, Germany
[6] Ludwig Maximihans Univ Munchen, Biomed Ctr, Inst Immunol, Planegg Martinsried, Germany
[7] Roche Pharma Res & Early Dev, Large Mol Res, Roche Innovat Ctr Munich, Penzberg, Germany
[8] Ludwig Maximilians Univ Munchen, Klinikum Univ Munchen, Med Klin & Poliklin 1, Munich, Germany
[9] Medigene Immunotherapies, Planegg Martinsried, Germany
[10] Ludwig Maximihans Univ Munchen, Gene Ctr, Munich, Germany
[11] Ludwig Maximihans Univ Munchen, Dept Biochem, Munich, Germany
[12] Ludwig Maximihans Univ Munchen, Max van Pettenkofer Inst Hyg & Med Mikrobiol, Munich, Germany
[13] Helmholtz Zentrum Munchen, Inst Dev Genet, Munich, Germany
[14] Tech Univ Munchen Weihenstephan, Neuherberg, Germany
[15] German Ctr Neurodegenerat Dis, Munich, Germany
[16] Munich Cluster Syst Neurol, Munich, Germany
[17] Helmholtz Zentrum Munchen, Inst Diabet & Obes, German Res Ctr Environm Hlth, Monocionai Antibody Core Facil, Neuherberg, Germany
[18] Helmholtz Zentrum Munchen, Res Unit Analyt Pathol, German Res Ctr Environm Hlth, Neuherberg, Germany
[19] Tech Univ Munich, Dept Med, Div Metab Dis, Munich, Germany
[20] Ludwig Maximihans Univ Munchen, Inst Informat, Munich, Germany
[21] Helmholtz Zentrum Munchen, Res Unit Prot Sci, German Res Ctr Environm Hlth, Neuherberg, Germany
[22] Helmholtz Zentrum Munchen, Res Unit Mol Immune Regulat, German Res Ctr Environm Hlth, Neuherberg, Germany
[23] German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany
[24] German Canc Res Ctr, Div Chron Inflammat & Canc F180, Heidelberg, Germany
关键词
NF-KAPPA-B; HELPER T-CELLS; MESSENGER-RNA; GENE-EXPRESSION; ROQUIN; FAMILY; INFLAMMATION; MACROPHAGES; MICRORNA; INNATE;
D O I
10.1084/jem.20181762
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:1700 / 1723
页数:24
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