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.
-
Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19NCBI Gene Expression Omnibus, GSE145926.
-
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.
Metrics
-
- 3,798
- views
-
- 935
- downloads
-
- 33
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
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
-
- Epidemiology and Global Health
- Medicine
- Microbiology and Infectious Disease
eLife has published the following articles on SARS-CoV-2 and COVID-19.
-
- Immunology and Inflammation
- Neuroscience
Somatic genetic heterogeneity resulting from post-zygotic DNA mutations is widespread in human tissues and can cause diseases, however, few studies have investigated its role in neurodegenerative processes such as Alzheimer’s disease (AD). Here, we report the selective enrichment of microglia clones carrying pathogenic variants, that are not present in neuronal, glia/stromal cells, or blood, from patients with AD in comparison to age-matched controls. Notably, microglia-specific AD-associated variants preferentially target the MAPK pathway, including recurrent CBL ring-domain mutations. These variants activate ERK and drive a microglia transcriptional program characterized by a strong neuro-inflammatory response, both in vitro and in patients. Although the natural history of AD-associated microglial clones is difficult to establish in humans, microglial expression of a MAPK pathway activating variant was previously shown to cause neurodegeneration in mice, suggesting that AD-associated neuroinflammatory microglial clones may contribute to the neurodegenerative process in patients.
