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Alliance"],"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:p>Inflammasomes are cytosolic innate immune sensors of pathogen infection and cellular damage that induce caspase-1\u2013mediated 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)-1\u03b2 production and caspase-1 activation in response to inflammasome stimulation. Mechanistically, RNH1 decreases pro-IL-1\u03b2 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 <jats:italic>Rnh1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> 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.<\/jats:p>","DOI":"10.26508\/lsa.202101226","type":"journal-article","created":{"date-parts":[[2022,3,7]],"date-time":"2022-03-07T15:40:14Z","timestamp":1646667614000},"page":"e202101226","update-policy":"https:\/\/doi.org\/10.26508\/lsa.crossmarkpolicy","source":"Crossref","is-referenced-by-count":15,"title":["LRR-protein RNH1 dampens the inflammasome activation and is associated with COVID-19 severity"],"prefix":"10.26508","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0752-4769","authenticated-orcid":true,"given":"Giuseppe","family":"Bombaci","sequence":"first","affiliation":[{"name":"Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland"},{"name":"Department for BioMedical Research, University of Bern, Bern, Switzerland"},{"name":"Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5653-8991","authenticated-orcid":true,"given":"Mayuresh Anant","family":"Sarangdhar","sequence":"additional","affiliation":[{"name":"Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland"},{"name":"Department for BioMedical Research, University of Bern, Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2924-6763","authenticated-orcid":true,"given":"Nicola","family":"Andina","sequence":"additional","affiliation":[{"name":"Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland"},{"name":"Department for BioMedical Research, University of Bern, Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aubry","family":"Tardivel","sequence":"additional","affiliation":[{"name":"Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland"},{"name":"Department for BioMedical Research, University of Bern, Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7026-7008","authenticated-orcid":true,"given":"Eric Chi-Wang","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Lausanne, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7758-6570","authenticated-orcid":true,"given":"Gillian M","family":"Mackie","sequence":"additional","affiliation":[{"name":"Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK"},{"name":"Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6324-661X","authenticated-orcid":true,"given":"Matthew","family":"Pugh","sequence":"additional","affiliation":[{"name":"Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6813-6348","authenticated-orcid":true,"given":"Vedat Burak","family":"Ozan","sequence":"additional","affiliation":[{"name":"Department for BioMedical Research, University of Bern, Bern, Switzerland"},{"name":"Department of Pulmonary Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yara","family":"Banz","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University of Bern, Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8057-3746","authenticated-orcid":true,"given":"Thibaud","family":"Spinetti","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7870-912X","authenticated-orcid":true,"given":"Cedric","family":"Hirzel","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Youd","sequence":"additional","affiliation":[{"name":"School of Medicine, Dentistry and Nursing, Forensic Medicine and Science. 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