Efferocytosis of SARS-CoV-2-infected dying cells impairs macrophage anti-inflammatory functions and clearance of apoptotic cells

Version of Record: July 7, 2022
Accepted Manuscript: June 6, 2022

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Ana Carolina G Salina

Douglas dos Santos

Tamara S Rodrigues

Marlon Fortes-Rocha

Edismauro G Freitas-Filho

Daniel L Alzamora-Terrel

Icaro MS Castro

Thais Fernanda Fraga-Silva

Mikhael HF de Lima

Daniele C Nascimento

Camila M Silva

Juliana E Toller-Kawahisa

Amanda Becerra

Samuel Oliveira

Diego B Caetite

Leticia Almeida

Adriene Y Ishimoto

Thais M Lima

Ronaldo B Martins

Flavio P Veras

Natália B do Amaral

Marcela C Giannini

Letícia P Bonjorno

Maria Isabel F Lopes

Maira N Benatti

Sabrina S Batah

Rodrigo C Santana

Fernando C Vilar

Maria Auxiliadora Martins

Rodrigo L Assad

Sergio CL deAlmeida

Fabiola R de Oliveira

Eurico Arruda Neto

Thiago M Cunha

Jose C Alves-Filho

Vania LD Bonato

Fernando Q Cunha

Alexandre T Fabro

Helder I Nakaya

Dario S Zamboni

Paulo Louzada-Junior

Renê DR de Oliveira

Larissa D Cunha

(2022)
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
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1. Related to
COVID-19: Locked in a pro-inflammatory state

Chiu Wang Chau, Ryohichi Sugimura

Insight Jul 7, 2022
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Abstract
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Article and author information

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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Article and author information

Author details

Ana Carolina G Salina

Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-3220-0413
Douglas dos Santos

Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.
Tamara S Rodrigues

Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.
Marlon Fortes-Rocha

Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-2055-2000
Edismauro G Freitas-Filho

Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1910-1085
Daniel L Alzamora-Terrel

Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.
Icaro MS Castro

Department of Clinical and Toxicological Analysis, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.
Thais Fernanda Fraga-Silva

Department of Biochemistry and Immunology, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.
Mikhael HF de Lima

Department of Pharmacology, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.
Daniele C Nascimento

Department of Pharmacology, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.
Camila M Silva

Department of Pharmacology, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.
Juliana E Toller-Kawahisa

Department of Pharmacology, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.
Amanda Becerra

Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.
Samuel Oliveira

Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.
Diego B Caetite

Department of Pharmacology, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.
Leticia Almeida

Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.
Adriene Y Ishimoto

Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.
Thais M Lima

Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5714-6057
Ronaldo B Martins

Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.
Flavio P Veras

Department of Pharmacology, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.
Natália B do Amaral

Division of Clinical Immunology, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.
Marcela C Giannini

Division of Clinical Immunology, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.
Letícia P Bonjorno

Division of Clinical Immunology, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.
Maria Isabel F Lopes

Division of Clinical Immunology, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.
Maira N Benatti

Department of Pathology and Forensic Medicine, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.
Sabrina S Batah

Department of Pathology and Forensic Medicine, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.
Rodrigo C Santana

Division of Clinical Immunology, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.
Fernando C Vilar

Division of Clinical Immunology, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.
Maria Auxiliadora Martins

Department of Pathology and Forensic Medicine, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.
Rodrigo L Assad

Division of Clinical Immunology, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-8430-8357
Sergio CL deAlmeida

Division of Clinical Immunology, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.
Fabiola R de Oliveira

Division of Clinical Immunology, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.
Eurico Arruda Neto

Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.
Thiago M Cunha

Department of Pharmacology, University of Sao Paulo, Ribeirao Preto, Brazil

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-1084-0065
Jose C Alves-Filho

Department of Pharmacology, University of Sao Paulo, Ribeirao Preto, Brazil

Competing interests
The authors declare that no competing interests exist.
Vania LD Bonato

Department of Biochemistry and Immunology, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.
Fernando Q Cunha

Department of Pharmacology, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.
Alexandre T Fabro

Department of Pathology and Forensic Medicine, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.
Helder I Nakaya

Department of Clinical and Toxicological Analysis, University of São Paulo, São Paulo, Brazil

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-5297-9108
Dario S Zamboni

Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of São Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-7856-7512
Paulo Louzada-Junior

Center of Research in Inflammatory Diseases, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.
Renê DR de Oliveira

Division of Clinical Immunology, University of Sao Paulo, Ribeirão Preto, Brazil

Competing interests
The authors declare that no competing interests exist.
Larissa D Cunha

Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil

For correspondence
larissacunha@usp.br

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1290-0263

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

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.