LRR protein RNH1 dampens the inflammasome activation and is associated with adverse clinical outcomes in COVID-19 patients

Bombaci, Giuseppe; Sarangdhar, Mayuresh Anant; Andina, Nicola; Tardivel, Aubry Bernard Maurice; Chi-Wang Yu, Eric; 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 (26 August 2021). LRR protein RNH1 dampens the inflammasome activation and is associated with adverse clinical outcomes in COVID-19 patients (In Press) (bioRxiv). Cold Spring Harbor Laboratory 10.1101/2021.04.12.438219

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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 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 proteins, attenuates inflammasome activation.
Deletion of RNH1 in macrophages increases IL-1b production and caspase-1 activation for
inflammasome stimuli. Mechanistically, RNH1 decreases pro-IL-1b expression and induces
proteasome-mediated caspase-1 degradation. Corroborating this, mouse models of
monosodium urate (MSU)-induced peritonitis and LPS-induced endotoxemia, which are
dependent on caspase-1, respectively show increased neutrophil infiltration and lethality in
Rnh1-/- mice compared to WT mice. Furthermore, RNH1 protein levels are negatively
correlated with inflammation and disease severity in hospitalized COVID-19 patients. We
propose that RNH1 is a new inflammasome regulator with relevance to COVID-19 severity

Item Type:

Working Paper

Division/Institute:

04 Faculty of Medicine > Department of Intensive Care, Emergency Medicine and Anaesthesiology (DINA) > Clinic of Intensive Care
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 Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Pneumology
04 Faculty of Medicine > Service Sector > Institute of Pathology > Cytopathology
04 Faculty of Medicine > Service Sector > Institute for Infectious Diseases
04 Faculty of Medicine > Service Sector > Institute of Pathology
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) > Forschungsbereich Mu50 > Forschungsgruppe Pneumologie (Erwachsene)
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) > 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)

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

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

Subjects:

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

Series:

bioRxiv

Publisher:

Cold Spring Harbor Laboratory

Language:

English

Submitter:

Pierrette Durand Lüthi

Date Deposited:

04 Feb 2022 10:33

Last Modified:

04 Feb 2022 10:42

Publisher DOI:

10.1101/2021.04.12.438219

BORIS DOI:

10.48350/164501

URI:

https://boris.unibe.ch/id/eprint/164501

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