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, Cédric; 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

[img]
Preview
Text
e202101226.full.pdf - Published Version
Available under License Creative Commons: Attribution (CC-BY).

Download (3MB) | Preview

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 Infectiology
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, Hirzel, Cédric, Schefold, Jörg Christian, Gazdhar, Amiq, Bonadies, Nicolas, Angelillo, Anne, 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:

05 Dec 2022 16:13

Publisher DOI:

10.26508/lsa.202101226

PubMed ID:

35256513

BORIS DOI:

10.48350/166895

URI:

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

Actions (login required)

Edit item Edit item
Provide Feedback