LRR-protein RNH1 dampens the inflammasome activation and is associated with COVID-19 severity.

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 -/- 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.

• Authors: Giuseppe Bombaci, Mayuresh Anant Sarangdhar, Nicola Andina, Aubry Tardivel, Eric Chi-Wang Yu, Gillian M Mackie, Matthew Pugh, Vedat Burak Ozan, Yara Banz, Thibaud Spinetti, Cedric Hirzel, Esther Youd, Joerg C Schefold, Graham Taylor, Amiq Gazdhar, Nicolas Bonadies, Anne Angelillo-Scherrer, Pascal Schneider, Kendle M Maslowski, Ramanjaneyulu Allam
• Journal: Life science alliance (Life Sci Alliance) Vol. 5 Issue 6 (06 2022) ISSN: 2575-1077 [Electronic] United States
• PMID: 35256513 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 Bombaci et al.

Chemical References

• Carrier Proteins
• Inflammasomes
• Leucine-Rich Repeat Proteins
• NF-kappa B
• NLR Family, Pyrin Domain-Containing 3 Protein
• NLRP3 protein, human
• RNH1 protein, human
• Caspase 1
• Proteasome Endopeptidase Complex

Topics

• Animals
• COVID-19 (immunology, pathology)
• Carrier Proteins (metabolism)
• Caspase 1 (metabolism)
• Humans
• Inflammasomes (metabolism)
• Leucine-Rich Repeat Proteins (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NF-kappa B (metabolism)
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Patient Acuity
• Proteasome Endopeptidase Complex (metabolism)