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

Giuseppe Bombaci, Mayuresh Anant Sarangdhar, Nicola Andina, Aubry Tardivel, Eric Chi Wang Yu, Gillian M. Mackie, Matthew Pugh, Vedat Burak Ozan, Yara Banz, Thibaud Spinetti, Cedric Hirzel, Esther Youd, Joerg C. Schefold, Graham Taylor, Amiq Gazdhar, Nicolas Bonadies, Anne Angelillo-Scherrer, Pascal Schneider, Kendle M. Maslowski, Ramanjaneyulu Allam

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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.

Original languageEnglish
JournalLife Science Alliance
Volume5
Issue number6
Early online date7 Mar 2022
DOIs
Publication statusE-pub ahead of print - 7 Mar 2022

ASJC Scopus subject areas

  • Ecology
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Plant Science
  • Health, Toxicology and Mutagenesis

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