tetano
Editor, Senior Moderator
Life Sci Alliance
. 2022 Mar 7;5(6):e202101226.
doi: 10.26508/lsa.202101226. Print 2022 Jun.
LRR-protein RNH1 dampens the inflammasome activation and is associated with COVID-19 severity
Giuseppe Bombaci[SUP] 1 2 3 [/SUP], Mayuresh Anant Sarangdhar[SUP] 1 2 [/SUP], Nicola Andina[SUP] 1 2 [/SUP], Aubry Tardivel[SUP] 1 2 [/SUP], Eric Chi-Wang Yu[SUP] 4 [/SUP], Gillian M Mackie[SUP] 5 6 [/SUP], Matthew Pugh[SUP] 5 [/SUP], Vedat Burak Ozan[SUP] 2 7 [/SUP], Yara Banz[SUP] 8 [/SUP], Thibaud Spinetti[SUP] 9 [/SUP], Cedric Hirzel[SUP] 10 [/SUP], Esther Youd[SUP] 11 [/SUP], Joerg C Schefold[SUP] 9 [/SUP], Graham Taylor[SUP] 5 [/SUP], Amiq Gazdhar[SUP] 2 7 [/SUP], Nicolas Bonadies[SUP] 1 2 [/SUP], Anne Angelillo-Scherrer[SUP] 1 2 [/SUP], Pascal Schneider[SUP] 4 [/SUP], Kendle M Maslowski[SUP] 5 6 [/SUP], Ramanjaneyulu Allam[SUP] 12 2 [/SUP]
Affiliations
Abstract
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 [SUP]-/-[/SUP] 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.
. 2022 Mar 7;5(6):e202101226.
doi: 10.26508/lsa.202101226. Print 2022 Jun.
LRR-protein RNH1 dampens the inflammasome activation and is associated with COVID-19 severity
Giuseppe Bombaci[SUP] 1 2 3 [/SUP], Mayuresh Anant Sarangdhar[SUP] 1 2 [/SUP], Nicola Andina[SUP] 1 2 [/SUP], Aubry Tardivel[SUP] 1 2 [/SUP], Eric Chi-Wang Yu[SUP] 4 [/SUP], Gillian M Mackie[SUP] 5 6 [/SUP], Matthew Pugh[SUP] 5 [/SUP], Vedat Burak Ozan[SUP] 2 7 [/SUP], Yara Banz[SUP] 8 [/SUP], Thibaud Spinetti[SUP] 9 [/SUP], Cedric Hirzel[SUP] 10 [/SUP], Esther Youd[SUP] 11 [/SUP], Joerg C Schefold[SUP] 9 [/SUP], Graham Taylor[SUP] 5 [/SUP], Amiq Gazdhar[SUP] 2 7 [/SUP], Nicolas Bonadies[SUP] 1 2 [/SUP], Anne Angelillo-Scherrer[SUP] 1 2 [/SUP], Pascal Schneider[SUP] 4 [/SUP], Kendle M Maslowski[SUP] 5 6 [/SUP], Ramanjaneyulu Allam[SUP] 12 2 [/SUP]
Affiliations
- PMID: 35256513
- DOI: 10.26508/lsa.202101226
Abstract
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 [SUP]-/-[/SUP] 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.