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 3

Identification of MAFB-binding elements in antiinflammatory M-MØ.

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Identification of MAFB-binding elements in antiinflammatory M-MØ. (A) Mo...
(A) Motif enrichment within ChIP-Seq MAFB peaks, with indication of the binding sequence position weight matrices, and their corresponding statistical significance. (B) Summary of the location of the identified MAFB-binding sites. (C) Comparison of the annotated genes corresponding to ChIP-Seq peaks and MAFB-dependent and MAFB-inhibited genes. (D) List of the 75 genes (75-gene set) with MAFB-binding elements with expression downregulated in ΔMAFB M-MØ (MAFB-inhibited). (E) Viewing alignments of the MAFB-binding profiles associated with CCL2 and IL10 genes using the Integrative Genomics Viewer. Each track illustrates a different sample and shows the peaks obtained in 2 independent experiments with anti-MAFB antibody (ChIP-Seq MAFB #1 and MAFB #2) and the corresponding input controls (input #1, input #2). (F) GSEA of the 75-gene set on the ranked comparison of the transcriptomes of M-MØ versus GM-MØ (GSE68061) (left panel), CHIR-M-MØ versus DMSO M-MØ (GSE185872) (middle panel), and MCTO M-MØ versus Control MØ (GSE155883) (right panel). Normalized Enrichment Score (NES) and FDR q value is indicated. (G) Relative mRNA expression of the indicated genes in ΔMAFB M-MØ and CNT M-MØ. Mean ± SEM of 4–6 independent samples are shown (*P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001). Statistical significance was calculated using paired t test (2-tailed). (H) Production of LGMN and CCL2 by ΔMAFB M-MØ and CNT M-MØ, as determined by ELISA. Mean ± SEM of 4 independent samples are shown (*P < 0.05; **P < 0.01). Statistical significance was calculated using paired ratio t test (2-tailed).