Abstract
Simple SummaryChronic inflammatory diseases account for up to 60% of deaths worldwide and, thus, are considered a great threat for human health by the World Health Organization. Nevertheless, acute inflammatory reactions are an integral part of the host defense against invading pathogens or injuries. To avoid excessive damage due to the persistence of a highly reactive environment, inflammations need to resolve in a coordinate and timely manner, ensuring for the immunological normalization of the affected tissues. Since post-transcriptional regulatory mechanisms are essential for effective resolution, the present review discusses the key role of the RNA-binding and post-transcriptional regulatory protein tristetraprolin in establishing resolution of inflammation.Inflammation is a crucial part of immune responses towards invading pathogens or tissue damage. While inflammatory reactions are aimed at removing the triggering stimulus, it is important that these processes are terminated in a coordinate manner to prevent excessive tissue damage due to the highly reactive inflammatory environment. Initiation of inflammatory responses was proposed to be regulated predominantly at a transcriptional level, whereas post-transcriptional modes of regulation appear to be crucial for resolution of inflammation. The RNA-binding protein tristetraprolin (TTP) interacts with AU-rich elements in the 3′ untranslated region of mRNAs, recruits deadenylase complexes and thereby facilitates degradation of its targets. As TTP regulates the mRNA stability of numerous inflammatory mediators, it was put forward as a crucial post-transcriptional regulator of inflammation. Here, we summarize the current understanding of the function of TTP with a specific focus on its role in adding to resolution of inflammation.
Highlights
Project Group Translational Medicine and Pharmacology TMP, Fraunhofer Institute for Molecular and Applied Ecology, 60596 Frankfurt, Germany
Though, macrophage populations change massively during inflammation, i.e., the original tissue resident macrophage population of mesodermal origin is rapidly reduced upon influx of neutrophils, both by cell death and emigration [30], and macrophages differentiating from infiltrating monocytes emerge to replenish the resident macrophage pool [31,32]
[69], which are commonly found within 3′ untranslated regions (3′ UTRs) of mRNAs and TTP to interact with adenosine and uridine (AU)-rich elements (AREs) [69], have been described as important RNA stability regulatory platforms0 for a broad group which are commonly
Summary
To prevent local tissue damage due to the sustained production of highly reactive inflammatory mediators, including reactive oxygen species and nitric oxide [5], Biology 2021, 10, 66. To prevent local tissue damage due to the sustained production of highly reactive inflammatory mediators, including reactive oxygen species and nitric oxide [5], and to reduce the riskthe of risk systemic effects,effects, inflammatory responses need toneed be resolved in a timely and to reduce of systemic inflammatory responses to be resolved in manner [6]. PRRs via damage-associated molecular patterns such as intracellular leased uponreleased necroticupon cell death [9,10]. They activate intracellular signalingincluding cascades including kinases (e.g., mitogen-activated protein kinasesand (MAPKs)). Though, macrophage populations change massively during inflammation, i.e., the original tissue resident macrophage population of mesodermal origin is rapidly reduced upon influx of neutrophils, both by cell death and emigration [30], and macrophages differentiating from infiltrating monocytes emerge to replenish the resident macrophage pool [31,32]
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