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Novel insights into double-stranded RNA-mediated immunopathology

Nature Reviews Immunology volume 24, pages 235–249 (2024)Cite this article

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Abstract

Recent progress in human and mouse genetics has transformed our understanding of the molecular mechanisms by which recognition of self double-stranded RNA (self-dsRNA) causes immunopathology. Novel mouse models recapitulate loss-of-function mutations in the RNA editing enzyme ADAR1 that are found in patients with Aicardi–Goutières syndrome (AGS) — a monogenic inflammatory disease associated with increased levels of type I interferon. Extensive analyses of the genotype–phenotype relationships in these mice have now firmly established a causal relationship between increased intracellular concentrations of endogenous immunostimulatory dsRNA and type I interferon-driven immunopathology. Activation of the dsRNA-specific immune sensor MDA5 perpetuates the overproduction of type I interferons, and chronic engagement of the interferon-inducible innate immune receptors PKR and ZBP1 by dsRNA drives immunopathology by activating an integrated stress response or by inducing excessive cell death. Biochemical and genetic data support a role for the p150 isoform of ADAR1 in the cytosol in suppressing the spontaneous, pathological response to self-dsRNA.

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Fig. 1: ADAR1 mutations in Aicardi–Goutières syndrome.
Fig. 2: ADAR1-p150 regulates the double-stranded RNA response.
Fig. 3: Negative feedback by ADAR1-p150 and positive feedback through interferon signalling set a threshold for double-stranded RNA-induced autoinflammation.

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Acknowledgements

The group of J.M. is supported by an Odysseus II Grant (G0H8618N), EOS INFLADIS (G0I5722N) and a junior research grant (G031022N) from the Research Foundation Flanders (FWO). R.d.R. is supported by a Ghent University BOF PhD fellowship. The authors thank the reviewers for their constructive criticism and important insight. Finally, the authors apologize to the scientists who moved the field of double-stranded RNA (dsRNA)-mediated immunity forward and whose important work we were not able to cite.

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  1. VIB-UGent Center for Inflammation Research, Ghent, Belgium

    Richard de Reuver & Jonathan Maelfait

  2. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium

    Richard de Reuver & Jonathan Maelfait

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R.d.R. and J.M. researched and discussed the cited literature. R.d.R. and J.M. wrote the main text. R.d.R. and J.M. generated the figures and supplementary tables.

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Glossary

Aicardi–Goutières syndrome

(AGS). Severe autoinflammatory childhood-onset encephalopathy, resulting from the activation of the nucleic acid receptors melanoma differentiation-associated protein 5 (MDA5) or cGAS by endogenous nucleic acids owing to mutations in one of the following genes involved in nucleic acid sensing or metabolism: ADAR, IFIH1, TREX1, SAMHD1, RNASEH2A, RNASEH2B, RNASEH2C, LSM11 or RNU7-1.

cis-Natural antisense transcripts

(cis-NATs). RNA molecules transcribed from (partially) overlapping sequences on opposing DNA strands within the same genomic locus containing regions of perfect complementarity, enabling the formation of double-stranded RNA (dsRNA) helices.

Integrated stress response

(ISR). An evolutionarily conserved cellular stress response induced by the eukaryotic translation initiation factor 2α (eIF2α) kinases, HRI, protein kinase R (PKR), PERK or GCN2, resulting in a global translational shutdown while increasing activating transcription factor 4 (ATF4)-dependent gene expression.

Short interspersed nuclear elements

(SINEs). A subclass of short (<1,000 bp), interspersed (non-tandem), non-autonomous retrotransposon-type repeat elements, containing sequences derived from RNA polymerase III-dependent transcripts including 7SL RNA, tRNA and 5S ribosomal RNA.

Z-Nucleic acid

Left-handed double-stranded DNA (dsDNA), double-stranded RNA (dsRNA) or hybrid DNA–RNA structures, characterized by a zig-zag-shaped (hence the name ‘Z’-nucleic acid) phosphodiester backbone containing purine–pyrimidine dinucleotide repeat sequences, which adopt alternating syn-conformations and anti-nucleobase conformations.

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de Reuver, R., Maelfait, J. Novel insights into double-stranded RNA-mediated immunopathology. Nat Rev Immunol 24, 235–249 (2024). https://doi.org/10.1038/s41577-023-00940-3

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