%0 Journal Article %A Giuseppe Bombaci %A Mayuresh Anant Sarangdhar %A Nicola Andina %A Aubry Tardivel %A Eric Chi-Wang Yu %A Gillian M Mackie %A Matthew Pugh %A Vedat Burak Ozan %A Yara Banz %A Thibaud Spinetti %A Cedric Hirzel %A Esther Youd %A Joerg C Schefold %A Graham Taylor %A Amiq Gazdhar %A Nicolas Bonadies %A Anne Angelillo-Scherrer %A Pascal Schneider %A Kendle M Maslowski %A Ramanjaneyulu Allam %T LRR-protein RNH1 dampens the inflammasome activation and is associated with COVID-19 severity %D 2022 %R 10.26508/lsa.202101226 %J Life Science Alliance %P e202101226 %V 5 %N 6 %X 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. %U https://www.life-science-alliance.org/content/lsa/5/6/e202101226.full.pdf