Bombaci, Giuseppe; Sarangdhar, Mayuresh Anant; Andina, Nicola; Tardivel, Aubry; Yu, Eric Chi-Wang; Mackie, Gillian M; Pugh, Matthew; Ozan, Vedat Burak; Banz, Yara; Spinetti, Thibaud; Hirzel, Cédric; Youd, Esther; Schefold, Joerg C; Taylor, Graham; Gazdhar, Amiq; Bonadies, Nicolas; Angelillo-Scherrer, Anne; Schneider, Pascal; Maslowski, Kendle M and Allam, Ramanjaneyulu (2022). LRR-protein RNH1 dampens the inflammasome activation and is associated with COVID-19 severity. Life science alliance, 5(6) EMBO Press 10.26508/lsa.202101226
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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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