MAFB shapes human monocyte–derived macrophage response to SARS-CoV-2 and controls severe COVID-19 biomarker expression
Miriam Simón-Fuentes, Israel Ríos, Cristina Herrero, Fátima Lasala, Nuria Labiod, Joanna Luczkowiak, Emilia Roy-Vallejo, Sara Fernández de Córdoba-Oñate, Pablo Delgado-Wicke, Matilde Bustos, Elena Fernández-Ruiz, Maria Colmenares, Amaya Puig-Kröger, Rafael Delgado, Miguel A. Vega, Ángel L. Corbí, Ángeles Domínguez-Soto
Miriam Simón-Fuentes, Israel Ríos, Cristina Herrero, Fátima Lasala, Nuria Labiod, Joanna Luczkowiak, Emilia Roy-Vallejo, Sara Fernández de Córdoba-Oñate, Pablo Delgado-Wicke, Matilde Bustos, Elena Fernández-Ruiz, Maria Colmenares, Amaya Puig-Kröger, Rafael Delgado, Miguel A. Vega, Ángel L. Corbí, Ángeles Domínguez-Soto
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Research Article COVID-19 Immunology

MAFB shapes human monocyte–derived macrophage response to SARS-CoV-2 and controls severe COVID-19 biomarker expression

Abstract

Monocyte-derived macrophages, the major source of pathogenic macrophages in COVID-19, are oppositely instructed by macrophage CSF (M-CSF) or granulocyte macrophage CSF (GM-CSF), which promote the generation of antiinflammatory/immunosuppressive MAFB+ (M-MØ) or proinflammatory macrophages (GM-MØ), respectively. The transcriptional profile of prevailing macrophage subsets in severe COVID-19 led us to hypothesize that MAFB shapes the transcriptome of pulmonary macrophages driving severe COVID-19 pathogenesis. We have now assessed the role of MAFB in the response of monocyte-derived macrophages to SARS-CoV-2 through genetic and pharmacological approaches, and we demonstrate that MAFB regulated the expression of the genes that define pulmonary pathogenic macrophages in severe COVID-19. Indeed, SARS-CoV-2 potentiated the expression of MAFB and MAFB-regulated genes in M-MØ and GM-MØ, where MAFB upregulated the expression of profibrotic and neutrophil-attracting factors. Thus, MAFB determines the transcriptome and functions of the monocyte-derived macrophage subsets that underlie pulmonary pathogenesis in severe COVID-19 and controls the expression of potentially useful biomarkers for COVID-19 severity.

Authors

Miriam Simón-Fuentes, Israel Ríos, Cristina Herrero, Fátima Lasala, Nuria Labiod, Joanna Luczkowiak, Emilia Roy-Vallejo, Sara Fernández de Córdoba-Oñate, Pablo Delgado-Wicke, Matilde Bustos, Elena Fernández-Ruiz, Maria Colmenares, Amaya Puig-Kröger, Rafael Delgado, Miguel A. Vega, Ángel L. Corbí, Ángeles Domínguez-Soto

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Figure 5

MAFB silencing drastically modifies the response of human macrophages to SARS-CoV-2.

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MAFB silencing drastically modifies the response of human macrophages to...
(A) Schematic representation of the transfection of M-MØ or GM-MØ with a MAFB-specific or control siRNA before SARS-CoV-2 exposure to generate ΔMAFB M-MØ SARS, ΔMAFB GM-MØ SARS, and their controls. (B) MAFB protein levels in ΔMAFB M-MØ SARS, ΔMAFB GM-MØ SARS, and their controls, as determined by Western blot, with vinculin as a loading control. Mean ± SEM of the MAFB/vinculin protein ratios from 3 independent experiments are shown (*P < 0.05; **P < 0.01; ***P < 0.001). Statistical significance was calculated using 1-way ANOVA with Tukey multiple-comparison test. A representative Western blot experiment is shown. (C) Summary of GSEA of MAFB-dependent genes, MAFB-inhibited genes (GSE155719), and the 75-gene set (GSE190589) on the ranked comparison of the transcriptomes of ΔMAFB M-MØ SARS and CNT M-MØ SARS (upper panel) or ΔMAFB GM-MØ SARS and CNT GM-MØ SARS (lower panel). Except where indicated, FDR q = 0.0 in each case. (D) Number of differentially expressed genes ([log2FC] > 1; Padj < 0.05) in SARS-CoV-2–infected macrophages (ΔMAFB M-MØ SARS and ΔMAFB GM-MØ SARS) relative to controls (CNT M-MØ SARS and CNT GM-MØ SARS). Gray columns indicate genes regulated in both M-MØ and GM-MØ. (E) Summary of GSEA of the gene sets characterizing macrophage subsets identified in severe COVID-19 (39, 48, 49) on the ranked comparison of the transcriptomes of ΔMAFB M-MØ SARS and CNT M-MØ SARS (left panel) or ΔMAF GM-MØ SARS versus CNT GM-MØ SARS (right panel). (F) GSEA of the genes strongly upregulated (log2[FC] > 3.58; Padj<0.05) in postmortem lung tissue from patients with COVID-19 (“COVID Lung Tissue UP”; GSE147507) (60) on the ranked comparison of the transcriptomes of ΔMAFB GM-MØ SARS versus CNT GM-MØ SARS. In all panels, FDR q values and the source of the original gene sets are indicated.