LRR protein RNH1 dampens the inflammasome activation and is associated with adverse clinical outcomes in COVID-19 patients

Bombaci, Giuseppe; Sarangdhar, Mayuresh Anant; Andina, Nicola; Tardivel, Aubry Bernard Maurice; Chi-Wang Yu, Eric; 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 (26 August 2021). LRR protein RNH1 dampens the inflammasome activation and is associated with adverse clinical outcomes in COVID-19 patients (In Press) (bioRxiv). Cold Spring Harbor Laboratory 10.1101/2021.04.12.438219

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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 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 proteins, attenuates inflammasome activation.
Deletion of RNH1 in macrophages increases IL-1b production and caspase-1 activation for
inflammasome stimuli. Mechanistically, RNH1 decreases pro-IL-1b expression and induces
proteasome-mediated caspase-1 degradation. Corroborating this, mouse models of
monosodium urate (MSU)-induced peritonitis and LPS-induced endotoxemia, which are
dependent on caspase-1, respectively show increased neutrophil infiltration and lethality in
Rnh1-/- mice compared to WT mice. Furthermore, RNH1 protein levels are negatively
correlated with inflammation and disease severity in hospitalized COVID-19 patients. We
propose that RNH1 is a new inflammasome regulator with relevance to COVID-19 severity

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