Persistent Oxidative Stress and Inflammasome Activation in CD14highCD16- Monocytes From COVID-19 Patients.

MedStar author(s):
Citation: Frontiers in Immunology. 12:799558, 2021.PMID: 35095880Institution: MedStar Washington Hospital CenterDepartment: Medicine/Infectious DiseasesForm of publication: Journal ArticleMedline article type(s): Journal Article | Research Support, N.I.H., IntramuralSubject headings: *COVID-19/me [Metabolism] | *Inflammasomes/me [Metabolism] | *Lipopolysaccharide Receptors/me [Metabolism] | *Monocytes/me [Metabolism] | *Oxidative Stress/ph [Physiology] | *Receptors, IgG/me [Metabolism] | Aged | Caspase 1/me [Metabolism] | COVID-19/pa [Pathology] | Female | GPI-Linked Proteins/me [Metabolism] | Humans | Interleukin-1beta/me [Metabolism] | Male | Middle Aged | Mitochondria/me [Metabolism] | Mitochondria/pa [Pathology] | Monocytes/pa [Pathology] | NLR Family, Pyrin Domain-Containing 3 Protein/me [Metabolism] | SARS-CoV-2/me [Metabolism] | Signal Transduction/ph [Physiology]Year: 2021Name of journal: Frontiers in immunologyAbstract: The poor outcome of the coronavirus disease-2019 (COVID-19), caused by SARS-CoV-2, is associated with systemic hyperinflammatory response and immunopathology. Although inflammasome and oxidative stress have independently been implicated in COVID-19, it is poorly understood whether these two pathways cooperatively contribute to disease severity. Herein, we found an enrichment of CD14highCD16- monocytes displaying inflammasome activation evidenced by caspase-1/ASC-speck formation in severe COVID-19 patients when compared to mild ones and healthy controls, respectively. Those cells also showed aberrant levels of mitochondrial superoxide and lipid peroxidation, both hallmarks of the oxidative stress response, which strongly correlated with caspase-1 activity. In addition, we found that NLRP3 inflammasome-derived IL-1beta secretion by SARS-CoV-2-exposed monocytes in vitro was partially dependent on lipid peroxidation. Importantly, altered inflammasome and stress responses persisted after short-term patient recovery. Collectively, our findings suggest oxidative stress/NLRP3 signaling pathway as a potential target for host-directed therapy to mitigate early COVID-19 hyperinflammation and also its long-term outcomes. Copyright (c) 2022 Lage, Amaral, Hilligan, Laidlaw, Rupert, Namasivayan, Rocco, Galindo, Kellogg, Kumar, Poon, Wortmann, Shannon, Hickman, Lisco, Manion, Sher and Sereti.All authors: Amaral EP, Galindo F, Hickman HD, Hilligan KL, Kellogg A, Kumar P, Lage SL, Laidlaw E, Lisco A, Manion M, Namasivayan S, Poon R, Rocco J, Rupert A, Sereti I, Shannon JP, Sher A, Wortmann GWOriginally published: Frontiers in Immunology. 12:799558, 2021.Fiscal year: FY2022Fiscal year of original publication: FY2022Digital Object Identifier: Date added to catalog: 2022-02-22
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Journal Article MedStar Authors Catalog Article 35095880 Available 35095880

The poor outcome of the coronavirus disease-2019 (COVID-19), caused by SARS-CoV-2, is associated with systemic hyperinflammatory response and immunopathology. Although inflammasome and oxidative stress have independently been implicated in COVID-19, it is poorly understood whether these two pathways cooperatively contribute to disease severity. Herein, we found an enrichment of CD14highCD16- monocytes displaying inflammasome activation evidenced by caspase-1/ASC-speck formation in severe COVID-19 patients when compared to mild ones and healthy controls, respectively. Those cells also showed aberrant levels of mitochondrial superoxide and lipid peroxidation, both hallmarks of the oxidative stress response, which strongly correlated with caspase-1 activity. In addition, we found that NLRP3 inflammasome-derived IL-1beta secretion by SARS-CoV-2-exposed monocytes in vitro was partially dependent on lipid peroxidation. Importantly, altered inflammasome and stress responses persisted after short-term patient recovery. Collectively, our findings suggest oxidative stress/NLRP3 signaling pathway as a potential target for host-directed therapy to mitigate early COVID-19 hyperinflammation and also its long-term outcomes. Copyright (c) 2022 Lage, Amaral, Hilligan, Laidlaw, Rupert, Namasivayan, Rocco, Galindo, Kellogg, Kumar, Poon, Wortmann, Shannon, Hickman, Lisco, Manion, Sher and Sereti.

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