Tristetraprolin‐driven regulatory circuit controls quality and timing of mRNA decay in inflammation

Molecular Systems Biology

Franz Kratochvill⁴  Christian Machacek⁴  Claus Vogl¹  Florian Ebner⁴  Vitaly Sedlyarov⁴  Andreas R Gruber²  Harald Hartweger⁴  Raimund Vielnascher¹  Marina Karaghiosoff¹  Thomas Rülicke³  Mathias Müller¹  Ivo Hofacker²  Roland Lang⁵ 

[1] Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria;Department of Theoretical Chemistry, University of Vienna, Vienna, Austria;Institute of Laboratory Animal Science and Biomodels Austria, University of Veterinary Medicine Vienna, Vienna, Austria;Max F. Perutz Laboratories, Center for Molecular Biology, University of Vienna, Vienna, Austria;Institute of Clinical Microbiology, Immunology and Hygiene, University Hospital Erlangen, Erlangen, Germany

关键词: immune homeostasis;    inflammation;    mRNA stability;    p38 MAPK;    tristetraprolin;   

DOI  :  10.1038/msb.2011.93

来源: Wiley

【 摘 要 】

Abstract

For a successful yet controlled immune response, cells need to specifically destabilize inflammatory mRNAs but prevent premature removal of those still used. The regulatory circuits controlling quality and timing in the global inflammatory mRNA decay are not understood. Here, we show that the mRNA-destabilizing function of the AU-rich element-binding protein tristetraprolin (TTP) is inversely regulated by the p38 MAPK activity profile such that after inflammatory stimulus the TTP-dependent decay is initially limited to few mRNAs. With time, the TTP-dependent decay gradually spreads resulting in cumulative elimination of one third of inflammation-induced unstable mRNAs in macrophages in vitro. We confirmed this sequential decay model in vivo since LPS-treated mice with myeloid TTP ablation exhibited similar cytokine dysregulation profile as macrophages. The mice were hypersensitive to LPS but otherwise healthy with no signs of hyperinflammation seen in conventional TTP knockout mice demonstrating the requirement for myeloid TTP in re-installment but not maintenance of immune homeostasis. These findings reveal a TTP- and p38 MAPK-dominated regulatory mechanism that is vital for balancing acute inflammation by a temporally and qualitatively controlled mRNA decay.

Synopsis

Inflammatory gene activation must be rigorously controlled to ensure a rapid, but transient, response. In this work, a regulatory circuit is revealed that governs the destabilization of inflammatory mRNAs and plays an essential role in re-establishing immune homeostasis after inflammatory stimulus.

• We describe a regulatory circuit that governs the sequential destabilization of inflammatory mRNAs. This circuit limits potentially deleterious inflammatory mRNA accumulation, yet it prevents premature removal of those mRNAs that are still needed.
• We show that the sequential destabilization of inflammatory mRNAs is driven by the continuous inverse coupling of p38 MAPK activity profile with the mRNA-destabilizing function of tristetraprolin (TTP) during the entire inflammatory response. This control mechanism ensures that with time, the TTP-dependent mRNA decay gradually spreads resulting in cumulative elimination of 30% of inflammation-induced unstable mRNAs in macrophages.
• We generated mice with myeloid cell-specific TTP deletion to provide evidence for the function of this regulatory circuit in vivo. These animals are hypersensitive to LPS and display a dysbalanced cytokine production whose pattern is agreement with our model of sequential destabilization the individual mRNAs by TTP.
• We propose that myeloid TTP is critically involved in the re-installment of immune homeostasis after inflammatory stimulus rather than in the maintenance of steady-state immune homeostasis.

【 授权许可】

CC BY-NC-SA   
Copyright © 2011 EMBO and Macmillan Publishers Limited

Creative Commons Attribution License, which permits distribution, and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation without specific permission.