Efferocytosis of SARS-CoV-2-infected dying cells impairs macrophage anti-inflammatory functions and clearance of apoptotic cells
- University of Sao Paulo, Brazil
- University of São Paulo, Brazil
Abstract
COVID-19 is a disease of dysfunctional immune responses, but the mechanisms triggering immunopathogenesis are not established. The functional plasticity of macrophages allows this cell type to promote pathogen elimination and inflammation or suppress inflammation and promote tissue remodeling and injury repair. During an infection, the clearance of dead and dying cells, a process named efferocytosis, can modulate the interplay between these contrasting functions. Here, we show that engulfment of SARS-CoV2-infected apoptotic cells exacerbates inflammatory cytokine production, inhibits the expression of efferocytic receptors, and impairs continual efferocytosis by macrophages. We also provide evidence supporting that lung monocytes and macrophages from severe COVID-19 patients have compromised efferocytic capacity. Our findings reveal that dysfunctional efferocytosis of SARS-CoV-2-infected cell corpses suppress macrophage anti-inflammation and efficient tissue repair programs and provide mechanistic insights for the excessive production of pro-inflammatory cytokines and accumulation of tissue damage associated with COVID-19 immunopathogenesis.
Data availability
Source data files containing the numerical values for graphs depicting flow cytometry, ELISA, CBA, RT-qPCR, and imaging quantification data are be uploaded as csv files. All code used for analysis is documented in the Methods section.
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Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19NCBI Gene Expression Omnibus, GSE145926.
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COVID-19 immune features revealed by a large-scale single-cell transcriptome atlas.NCBI Gene Expression Omnibus, GSE158055.
Article and author information
Author details
Ana Carolina G Salina
Marlon Fortes-Rocha
Edismauro G Freitas-Filho
Funding
Fundação de Amparo à Pesquisa do Estado de São Paulo (2018/25559-4)
- Larissa D Cunha
Fundação de Amparo à Pesquisa do Estado de São Paulo (2020/05288-6)
- Larissa D Cunha
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (88887.507253/2020-00)
- Dario S Zamboni
Conselho Nacional de Desenvolvimento Científico e Tecnológico (434538/2018-3)
- Larissa D Cunha
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: The procedures followed in the study were approved by the Research Ethics Committee of Hospital das Clínicas de Ribeirão Preto (CEP-FMRP/USP) and by the National Ethics Committee, Brazil (Comissão Nacional de Ética em Pesquisa (CONEP), protocols 30248420.9.0000.5440 and 39722020.9.0000.5440. Written informed consent was obtained from recruited donors.Ultrasound-guided minimally invasive autopsies for COVID-19 deceased patients were approved by the Research Ethics Committee of Hospital das Clínicas de Ribeirão Preto (CEP, protocol no. 4.089.567).
Copyright
© 2022, Salina et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Efferocytosis of SARS-CoV-2-infected dying cells impairs macrophage anti-inflammatory functions and clearance of apoptotic cells
eLife 11:e74443.
https://doi.org/10.7554/eLife.74443
Further reading
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Airway macrophages (AM) are the predominant immune cell in the lung and play a crucial role in preventing infection, making them a target for host directed therapy. Macrophage effector functions are associated with cellular metabolism. A knowledge gap remains in understanding metabolic reprogramming and functional plasticity of distinct human macrophage subpopulations, especially in lung resident AM. We examined tissue-resident AM and monocyte-derived macrophages (MDM; as a model of blood derived macrophages) in their resting state and after priming with IFN-γ or IL-4 to model the Th1/Th2 axis in the lung. Human macrophages, regardless of origin, had a strong induction of glycolysis in response to IFN-γ or upon stimulation. IFN-γ significantly enhanced cellular energetics in both AM and MDM by upregulating both glycolysis and oxidative phosphorylation. Upon stimulation, AM do not decrease oxidative phosphorylation unlike MDM which shift to ‘Warburg’-like metabolism. IFN-γ priming promoted cytokine secretion in AM. Blocking glycolysis with 2-deoxyglucose significantly reduced IFN-γ driven cytokine production in AM, indicating that IFN-γ induces functional plasticity in human AM, which is mechanistically mediated by glycolysis. Directly comparing responses between macrophages, AM were more responsive to IFN-γ priming and dependent on glycolysis for cytokine secretion than MDM. Interestingly, TNF production was under the control of glycolysis in AM and not in MDM. MDM exhibited glycolysis-dependent upregulation of HLA-DR and CD40, whereas IFN-γ upregulated HLA-DR and CD40 on AM independently of glycolysis. These data indicate that human AM are functionally plastic and respond to IFN-γ in a manner distinct from MDM. These data provide evidence that human AM are a tractable target for inhalable immunomodulatory therapies for respiratory diseases.
