TY - JOUR
AU - Bombaci, Giuseppe
AU - Sarangdhar, Mayuresh Anant
AU - Andina, Nicola
AU - Tardivel, Aubry
AU - Yu, Eric Chi-Wang
AU - Mackie, Gillian M.
AU - Pugh, Matthew
AU - Ozan, Vedat Burak
AU - Banz, Yara
AU - Spinetti, Thibaud
AU - Hirzel, Cedric
AU - Youd, Esther
AU - Schefold, Joerg C.
AU - Taylor, Graham
AU - Gazdhar, Amiq
AU - Bonadies, Nicolas
AU - Angelillo-Scherrer, Anne
AU - Schneider, Pascal
AU - Maslowski, Kendle M.
AU - Allam, Ramanjaneyulu
PY - 2022
DA - March
TI - LRR-protein RNH1 dampens the inflammasome activation and is associated with COVID-19 severity
JO - Life Science Alliance
VL - 5
IS - 6
DO - https://doi.org/10.26508/lsa.202101226
AB - 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.
PB - Life Science Alliance
UR - http://eprints.gla.ac.uk/267291/
KW - Coronavirus (COVID-19)
ER