Hydroxychloroquine attenuates double-stranded RNA-stimulated hyper-phosphorylation of tristetraprolin/ZFP36 and AU-rich mRNA stabilization
et al., Immunology, doi:10.1111/imm.13835, Jul 2024
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In vitro study showing that HCQ reduces inflammation by inhibiting the double-stranded RNA-stimulated phosphorylation of tristetraprolin (TTP) and decreasing the stability of AU-rich mRNAs. This suggests that HCQ could mitigate excessive inflammatory responses, such as cytokine storms, which are characteristic of severe COVID-19 and other viral infections.
39 preclinical studies support the efficacy of HCQ for COVID-19:
1.
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13.
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21.
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22.
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24.
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33.
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34.
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Hitti et al., 24 Jul 2024, peer-reviewed, 5 authors.
In vitro studies are an important part of preclinical research, however results may be very different in vivo.
Hydroxychloroquine attenuates double‐stranded RNA‐stimulated hyper‐phosphorylation of tristetraprolin/ZFP36 and AU‐rich mRNA stabilization
Immunology, doi:10.1111/imm.13835
The human innate immune system recognizes dsRNA as a pathogen-associated molecular pattern that induces a potent inflammatory response. The primary source of pathogenic dsRNA is cells infected with replicating viruses, but can also be released from uninfected necrotic cells. Here, we show that the dsRNA poly(I:C) challenge in human macrophages activates the p38 MAPK-MK2 signalling pathway and subsequently the phosphorylation of tristetraprolin (TTP/ZFP36). The latter is an mRNA decaypromoting protein that controls the stability of AU-rich mRNAs (AREs) that code for many inflammatory mediators. Hydroxychloroquine (HCQ), a common anti-malaria drug, is used to treat inflammatory and autoimmune disorders and, controversially, during acute COVID-19 disease. We found that HCQ reduced the dsRNA-dependent phosphorylation of p38 MAPK and its downstream kinase MK2. Subsequently, HCQ reduced the abundance and protein stability of the inactive (phosphorylated) form of TTP. HCQ reduced the levels and the mRNA stability of poly (I:C)-induced cytokines and inflammatory mRNAs like TNF, IL-6, COX-2, and IL-8 in THP-1 and primary blood monocytes. Our results demonstrate a new mechanism of the anti-inflammatory role of HCQ at post-transcriptional level (TTP phosphorylation) in a model of dsRNA activation, which usually occurs in viral infections or RNA release from necrotic tissue.
AUTHOR CONTRIBUTIONS Concept, Design, Data analysis, and Writing: (E. Hitti, K. Khabar); Performance of experiments and data acquisition (Z. Muazzen, W. Moghrabi, S. Al-Yahya). All authors contributed to the article and approved the submitted version.
CONFLICT OF INTEREST STATEMENT The authors report no conflicts of interest.
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