LRR-protein RNH1 dampens the inflammasome activation and is associated with COVID-19 severity
Male
Mice, Knockout
0301 basic medicine
Proteasome Endopeptidase Complex
Inflammasomes
Caspase 1
NF-kappa B
Patient Acuity
COVID-19
610 Medicine & health
Leucine-Rich Repeat Proteins
3. Good health
Mice, Inbred C57BL
Mice
03 medical and health sciences
NLR Family, Pyrin Domain-Containing 3 Protein
570 Life sciences; biology
Animals
Humans
Animals; COVID-19/immunology; COVID-19/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
Carrier Proteins
Research Articles
DOI:
10.26508/lsa.202101226
Publication Date:
2022-03-07T15:40:14Z
AUTHORS (20)
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.
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