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

Bombaci, Giuseppe; Sarangdhar, Mayuresh Anant; Andina, Nicola; Tardivel, Aubry; Yu, Eric Chi-Wang; Mackie, Gillian M; Pugh, Matthew; Ozan, Vedat Burak; Banz, Yara; Spinetti, Thibaud; Hirzel, Cedric; Youd, Esther; Schefold, Joerg C; Taylor, Graham; Gazdhar, Amiq; Bonadies, Nicolas; Angelillo-Scherrer, Anne; Schneider, Pascal; Maslowski, Kendle M and Allam, Ramanjaneyulu (2022). LRR-protein RNH1 dampens the inflammasome activation and is associated with COVID-19 severity. Life science alliance, 5(6) EMBO Press 10.26508/lsa.202101226

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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 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Haematology and Central Haematological Laboratory
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Hämatologie (Erwachsene)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Mu50 > Forschungsgruppe Pneumologie (Erwachsene)
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Pneumology
04 Faculty of Medicine > Department of Intensive Care, Emergency Medicine and Anaesthesiology (DINA) > Clinic of Intensive Care
04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hämatologie / Onkologie (Pädiatrie)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hämatologie / Onkologie (Pädiatrie)

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Bombaci, Giuseppe; Sarangdhar, Mayuresh Anant; Andina, Nicola; Tardivel, Aubry Bernard Maurice; Ozan, Vedat Burak; Banz Wälti, Yara Sarah; Spinetti, Thibaud; Schefold, Jörg Christian; Gazdhar, Amiq; Bonadies, Nicolas; Angelillo, Anne and Allam, Ramanjaneyulu

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

2575-1077

Publisher:

EMBO Press

Language:

English

Submitter:

Pubmed Import

Date Deposited:

09 Mar 2022 10:22

Last Modified:

09 Mar 2022 10:31

Publisher DOI:

10.26508/lsa.202101226

PubMed ID:

35256513

BORIS DOI:

10.48350/166895

URI:

https://boris.unibe.ch/id/eprint/166895

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