An epithelial-immune circuit amplifies inflammasome and IL-6 responses to SARS-CoV-2.

Autor:	Barnett KC; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Xie Y; Department of Computational Mathematics, Science and Engineering, Michigan State University, East Lansing, MI 48824, USA; Department of Statistics and Probability, Michigan State University, East Lansing, MI 48824, USA., Asakura T; Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Song D; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Liang K; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Oral and Craniofacial Biomedicine Program, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Taft-Benz SA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Guo H; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Yang S; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Okuda K; Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Gilmore RC; Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Loome JF; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Oguin Iii TH; Duke Human Vaccine Institute, Durham, NC 27701, USA., Sempowski GD; Duke Human Vaccine Institute, Durham, NC 27701, USA., Randell SH; Department of Statistics and Probability, Michigan State University, East Lansing, MI 48824, USA., Heise MT; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Lei YL; Department of Periodontics and Oral Medicine, Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48104, USA; Department of Otolaryngology-Head and Neck Surgery, Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA., Boucher RC; Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Ting JP; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: jenny_ting@med.unc.edu.
Jazyk:	angličtina
Zdroj:	Cell host & microbe [Cell Host Microbe] 2023 Feb 08; Vol. 31 (2), pp. 243-259.e6. Date of Electronic Publication: 2022 Dec 09.
DOI:	10.1016/j.chom.2022.12.005
Abstrakt:	Elevated levels of cytokines IL-1β and IL-6 are associated with severe COVID-19. Investigating the underlying mechanisms, we find that while primary human airway epithelia (HAE) have functional inflammasomes and support SARS-CoV-2 replication, they are not the source of IL-1β released upon infection. In leukocytes, the SARS-CoV-2 E protein upregulates inflammasome gene transcription via TLR2 to prime, but not activate, inflammasomes. SARS-CoV-2-infected HAE supply a second signal, which includes genomic and mitochondrial DNA, to stimulate leukocyte IL-1β release. Nuclease treatment, STING, and caspase-1 inhibition but not NLRP3 inhibition blocked leukocyte IL-1β release. After release, IL-1β stimulates IL-6 secretion from HAE. Therefore, infection alone does not increase IL-1β secretion by either cell type. Rather, bi-directional interactions between the SARS-CoV-2-infected epithelium and immune bystanders stimulates both IL-1β and IL-6, creating a pro-inflammatory cytokine circuit. Consistent with these observations, patient autopsy lungs show elevated myeloid inflammasome gene signatures in severe COVID-19. Competing Interests: Declaration of interests J.P.-Y.T. is a cofounder of IMMvention Therapeutix, which works on inflammasome inhibitors. (Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu