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

Abstract

Inflammasomes are cytosolic innate immune sensors that, upon activation, induce caspase-1 mediated inflammation. Although inflammation is protective, uncontrolled excessive inflammation can cause inflammatory diseases and is also detrimental in COVID-19 infection. 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 NOD-like receptor family pyrin domain (PYD)-containing (NLRP) proteins, attenuates inflammasome activation. Mechanistically, RNH1 decreased pro-IL1b expression and induced 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 showed increased neutrophil infiltration and lethality in Rnh1-/- mice compared to WT mice. Further, RNH1 protein levels were 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.

Emerging Insights on Caspases in COVID-19 Pathogenesis, Sequelae, and Directed Therapies

“…In human monocytes, caspase-1 activation along with IL-1β production and pyroptosis is observed in both SARS-CoV-2 infected ex vivo and from infected ICU patients ( 86 ). RNH1 protein, an inhibitor of inflammasome activation through proteasome-mediated degradation of caspase-1, is increased in the blood and lung biopsies from individuals with COVID-19 and is negatively associated with SARS-CoV-2-mediated inflammation and adverse clinical outcomes ( 87 ). In vitro , SARS-CoV-2 infected human monocytes demonstrate pyroptotic activity, which was associated with caspase-1 activation, IL-1β production, GSDMD cleavage, and enhanced pro-inflammatory cytokine levels ( 86 ).…”