TY - JOUR T1 - LRR-protein RNH1 dampens the inflammasome activation and is associated with COVID-19 severity JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.202101226 VL - 5 IS - 6 SP - e202101226 AU - Giuseppe Bombaci AU - Mayuresh Anant Sarangdhar AU - Nicola Andina AU - Aubry Tardivel AU - Eric Chi-Wang Yu AU - Gillian M Mackie AU - Matthew Pugh AU - Vedat Burak Ozan AU - Yara Banz AU - Thibaud Spinetti AU - Cedric Hirzel AU - Esther Youd AU - Joerg C Schefold AU - Graham Taylor AU - Amiq Gazdhar AU - Nicolas Bonadies AU - Anne Angelillo-Scherrer AU - Pascal Schneider AU - Kendle M Maslowski AU - Ramanjaneyulu Allam Y1 - 2022/06/01 UR - https://www.life-science-alliance.org/content/5/6/e202101226.abstract N2 - 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. ER -