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Activation and Measurement of NLRP3 Inflammasome Activity Using IL-1β in Human Monocyte-derived Dendritic Cells
Published on: May 22, 2014
Persistent Oxidative Stress and Inflammasome Activation in CD14highCD16- Monocytes From COVID-19 Patients
Silvia Lucena Lage1, Eduardo Pinheiro Amaral2, Kerry L Hilligan2,3
1HIV Pathogenesis Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States.
Insights
Severe COVID-19 involves inflammasome activation and oxidative stress in monocytes. These pathways are linked and persist post-recovery, suggesting a therapeutic target for hyperinflammation.
Area of Science:
- Immunology
- Molecular Biology
- Pathophysiology
Background:
- COVID-19 severity is linked to systemic hyperinflammation and immunopathology.
- Both inflammasome activation and oxidative stress are implicated in COVID-19, but their cooperative role is unclear.
Purpose of the Study:
- To investigate the interplay between inflammasome and oxidative stress pathways in COVID-19 severity.
- To identify potential therapeutic targets for mitigating COVID-19-associated hyperinflammation.
Main Methods:
- Flow cytometry to analyze monocyte subsets (CD14highCD16-) in COVID-19 patients.
- Assessed inflammasome activation (caspase-1/ASC-speck) and oxidative stress markers (mitochondrial superoxide, lipid peroxidation).
- In vitro studies on SARS-CoV-2-exposed monocytes to examine IL-1β secretion and pathway dependency.
Main Results:
- Severe COVID-19 patients exhibited increased CD14highCD16- monocytes with activated inflammasomes and elevated oxidative stress markers.
- Oxidative stress markers strongly correlated with caspase-1 activity.
- NLRP3 inflammasome-derived IL-1β secretion was partially dependent on lipid peroxidation and persisted post-recovery.
Conclusions:
- Cooperative activation of oxidative stress and NLRP3 inflammasome pathways contributes to COVID-19 severity.
- These altered pathways persist after recovery, indicating potential long-term implications.
- Targeting the oxidative stress/NLRP3 signaling pathway may offer a host-directed therapeutic strategy for COVID-19.
Abstract:
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-1β 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.
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