LRR-protein RNH1 dampens the inflammasome activation and is associated with COVID-19 severity - Repository

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: https://doi.org/10.26508/lsa.202101226

Abstract

Inflammasomes are cytosolic innate immune sensors of pathogen infection and cellular damage that induce caspase-1–mediated inflammation upon activation. Although inflammation is protective, uncontrolled excessive inflammation can cause inflammatory diseases and can be detrimental, such as in coronavirus disease (COVID-19). However, the underlying mechanisms that control inflammasome activation are incompletely understood. Here we report that the leucine-rich repeat (LRR) protein ribonuclease inhibitor (RNH1), which shares homology with LRRs of NLRP (nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing) proteins, attenuates inflammasome activation. Deletion of RNH1 in macrophages increases interleukin (IL)-1β production and caspase-1 activation in response to inflammasome stimulation. Mechanistically, RNH1 decreases pro-IL-1β expression and induces proteasome-mediated caspase-1 degradation. Corroborating this, mouse models of monosodium urate (MSU)-induced peritonitis and lipopolysaccharide (LPS)-induced endotoxemia, which are dependent on caspase-1, respectively, show increased neutrophil infiltration and lethality in Rnh1−/− mice compared with wild-type mice. Furthermore, RNH1 protein levels were negatively related with disease severity and inflammation in hospitalized COVID-19 patients. We propose that RNH1 is a new inflammasome regulator with relevance to COVID-19 severity.

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This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).

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Bombaci, G., Sarangdhar, M., Andina, N., Tardivel, A., Yu, E., Mackie, G., Pugh, M., Ozan, V., Banz, Y., Spinetti, T., Hirzel, C., Youd, E., Schefold, J., Taylor, G., Gazdhar, A., Bonadies, N., Angelillo-Scherrer, A., Schneider, P., Maslowski, K. & Allam, R. 2022, 'LRR-protein RNH1 dampens the inflammasome activation and is associated with COVID-19 severity', Life Science Alliance, 5(6), article no: e202101226. https://doi.org/10.26508/lsa.202101226

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DOI: https://doi.org/10.26508/lsa.202101226

Repository URI: http://eprints.gla.ac.uk/267291/