SARS-CoV-2/ACE2 Interaction Suppresses IRAK-M Expression and Promotes Pro-Inflammatory Cytokine Production in Macrophages
The major cause of death in SARS-CoV-2 infected patients is due to de-regulation of the innate immune system and development of cytokine storm. SARS-CoV-2 infects multiple cell types in the lung, including macrophages, by engagement of its spike (S) protein on angiotensin converting enzyme 2 (ACE2)...
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Frontiers Media S.A.
2021-06-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.683800/full |
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| author | Ioanna Pantazi Ioanna Pantazi Ahmed A. Al-Qahtani Ahmed A. Al-Qahtani Fatimah S Alhamlan Fatimah S Alhamlan Hani Alothaid Sabine Matou-Nasri George Sourvinos Eleni Vergadi Christos Tsatsanis Christos Tsatsanis |
| author_facet | Ioanna Pantazi Ioanna Pantazi Ahmed A. Al-Qahtani Ahmed A. Al-Qahtani Fatimah S Alhamlan Fatimah S Alhamlan Hani Alothaid Sabine Matou-Nasri George Sourvinos Eleni Vergadi Christos Tsatsanis Christos Tsatsanis |
| author_sort | Ioanna Pantazi |
| collection | DOAJ |
| description | The major cause of death in SARS-CoV-2 infected patients is due to de-regulation of the innate immune system and development of cytokine storm. SARS-CoV-2 infects multiple cell types in the lung, including macrophages, by engagement of its spike (S) protein on angiotensin converting enzyme 2 (ACE2) receptor. ACE2 receptor initiates signals in macrophages that modulate their activation, including production of cytokines and chemokines. IL-1R-associated kinase (IRAK)-M is a central regulator of inflammatory responses regulating the magnitude of TLR responsiveness. Aim of the work was to investigate whether SARS-CoV-2 S protein-initiated signals modulate pro-inflammatory cytokine production in macrophages. For this purpose, we treated PMA-differentiated THP-1 human macrophages with SARS-CoV-2 S protein and measured the induction of inflammatory mediators including IL6, TNFα, IL8, CXCL5, and MIP1a. The results showed that SARS-CoV-2 S protein induced IL6, MIP1a and TNFα mRNA expression, while it had no effect on IL8 and CXCL5 mRNA levels. We further examined whether SARS-CoV-2 S protein altered the responsiveness of macrophages to TLR signals. Treatment of LPS-activated macrophages with SARS-CoV-2 S protein augmented IL6 and MIP1a mRNA, an effect that was evident at the protein level only for IL6. Similarly, treatment of PAM3csk4 stimulated macrophages with SARS-CoV-2 S protein resulted in increased mRNA of IL6, while TNFα and MIP1a were unaffected. The results were confirmed in primary human peripheral monocytic cells (PBMCs) and isolated CD14+ monocytes. Macrophage responsiveness to TLR ligands is regulated by IRAK-M, an inactive IRAK kinase isoform. Indeed, we found that SARS-CoV-2 S protein suppressed IRAK-M mRNA and protein expression both in THP1 macrophages and primary human PBMCs and CD14+ monocytes. Engagement of SARS-CoV-2 S protein with ACE2 results in internalization of ACE2 and suppression of its activity. Activation of ACE2 has been previously shown to induce anti-inflammatory responses in macrophages. Treatment of macrophages with the ACE2 activator DIZE suppressed the pro-inflammatory action of SARS-CoV-2. Our results demonstrated that SARS-CoV-2/ACE2 interaction rendered macrophages hyper-responsive to TLR signals, suppressed IRAK-M and promoted pro-inflammatory cytokine expression. Thus, activation of ACE2 may be a potential anti-inflammatory therapeutic strategy to eliminate the development of cytokine storm observed in COVID-19 patients. |
| first_indexed | 2024-12-14T19:05:16Z |
| format | Article |
| id | doaj.art-68c2e831848946b6abd7e79c9ea26b3c |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-14T19:05:16Z |
| publishDate | 2021-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-68c2e831848946b6abd7e79c9ea26b3c2022-12-21T22:50:52ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-06-011210.3389/fimmu.2021.683800683800SARS-CoV-2/ACE2 Interaction Suppresses IRAK-M Expression and Promotes Pro-Inflammatory Cytokine Production in MacrophagesIoanna Pantazi0Ioanna Pantazi1Ahmed A. Al-Qahtani2Ahmed A. Al-Qahtani3Fatimah S Alhamlan4Fatimah S Alhamlan5Hani Alothaid6Sabine Matou-Nasri7George Sourvinos8Eleni Vergadi9Christos Tsatsanis10Christos Tsatsanis11Laboratory of Clinical Chemistry, Medical School, University of Crete, Heraklion, GreeceDepartment of Pediatrics, Medical School, University of Crete, Heraklion, GreeceDepartment of Infection and Immunity, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi ArabiaDepartment of Microbiology and Immunology, College of Medicine, Alfaisal University, Riyadh, Saudi ArabiaDepartment of Infection and Immunity, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi ArabiaDepartment of Microbiology and Immunology, College of Medicine, Alfaisal University, Riyadh, Saudi ArabiaDepartment of Basic Sciences, Faculty of Applied Medical Sciences, Al-Baha University, Al-Baha, Saudi ArabiaCell and Gene Therapy Group, Medical Genomics Research Department, King Abdullah International Medical Research Center, Riyadh, Saudi ArabiaLaboratory of Virology, Medical School, University of Crete, Heraklion, GreeceDepartment of Pediatrics, Medical School, University of Crete, Heraklion, GreeceLaboratory of Clinical Chemistry, Medical School, University of Crete, Heraklion, GreeceInstitute of Molecular Biology and Biotechnology, FORTH, Heraklion, GreeceThe major cause of death in SARS-CoV-2 infected patients is due to de-regulation of the innate immune system and development of cytokine storm. SARS-CoV-2 infects multiple cell types in the lung, including macrophages, by engagement of its spike (S) protein on angiotensin converting enzyme 2 (ACE2) receptor. ACE2 receptor initiates signals in macrophages that modulate their activation, including production of cytokines and chemokines. IL-1R-associated kinase (IRAK)-M is a central regulator of inflammatory responses regulating the magnitude of TLR responsiveness. Aim of the work was to investigate whether SARS-CoV-2 S protein-initiated signals modulate pro-inflammatory cytokine production in macrophages. For this purpose, we treated PMA-differentiated THP-1 human macrophages with SARS-CoV-2 S protein and measured the induction of inflammatory mediators including IL6, TNFα, IL8, CXCL5, and MIP1a. The results showed that SARS-CoV-2 S protein induced IL6, MIP1a and TNFα mRNA expression, while it had no effect on IL8 and CXCL5 mRNA levels. We further examined whether SARS-CoV-2 S protein altered the responsiveness of macrophages to TLR signals. Treatment of LPS-activated macrophages with SARS-CoV-2 S protein augmented IL6 and MIP1a mRNA, an effect that was evident at the protein level only for IL6. Similarly, treatment of PAM3csk4 stimulated macrophages with SARS-CoV-2 S protein resulted in increased mRNA of IL6, while TNFα and MIP1a were unaffected. The results were confirmed in primary human peripheral monocytic cells (PBMCs) and isolated CD14+ monocytes. Macrophage responsiveness to TLR ligands is regulated by IRAK-M, an inactive IRAK kinase isoform. Indeed, we found that SARS-CoV-2 S protein suppressed IRAK-M mRNA and protein expression both in THP1 macrophages and primary human PBMCs and CD14+ monocytes. Engagement of SARS-CoV-2 S protein with ACE2 results in internalization of ACE2 and suppression of its activity. Activation of ACE2 has been previously shown to induce anti-inflammatory responses in macrophages. Treatment of macrophages with the ACE2 activator DIZE suppressed the pro-inflammatory action of SARS-CoV-2. Our results demonstrated that SARS-CoV-2/ACE2 interaction rendered macrophages hyper-responsive to TLR signals, suppressed IRAK-M and promoted pro-inflammatory cytokine expression. Thus, activation of ACE2 may be a potential anti-inflammatory therapeutic strategy to eliminate the development of cytokine storm observed in COVID-19 patients.https://www.frontiersin.org/articles/10.3389/fimmu.2021.683800/fullmacrophagesACE2COVID-19SARS-CoV-2IRAK-Minflammation |
| spellingShingle | Ioanna Pantazi Ioanna Pantazi Ahmed A. Al-Qahtani Ahmed A. Al-Qahtani Fatimah S Alhamlan Fatimah S Alhamlan Hani Alothaid Sabine Matou-Nasri George Sourvinos Eleni Vergadi Christos Tsatsanis Christos Tsatsanis SARS-CoV-2/ACE2 Interaction Suppresses IRAK-M Expression and Promotes Pro-Inflammatory Cytokine Production in Macrophages Frontiers in Immunology macrophages ACE2 COVID-19 SARS-CoV-2 IRAK-M inflammation |
| title | SARS-CoV-2/ACE2 Interaction Suppresses IRAK-M Expression and Promotes Pro-Inflammatory Cytokine Production in Macrophages |
| title_full | SARS-CoV-2/ACE2 Interaction Suppresses IRAK-M Expression and Promotes Pro-Inflammatory Cytokine Production in Macrophages |
| title_fullStr | SARS-CoV-2/ACE2 Interaction Suppresses IRAK-M Expression and Promotes Pro-Inflammatory Cytokine Production in Macrophages |
| title_full_unstemmed | SARS-CoV-2/ACE2 Interaction Suppresses IRAK-M Expression and Promotes Pro-Inflammatory Cytokine Production in Macrophages |
| title_short | SARS-CoV-2/ACE2 Interaction Suppresses IRAK-M Expression and Promotes Pro-Inflammatory Cytokine Production in Macrophages |
| title_sort | sars cov 2 ace2 interaction suppresses irak m expression and promotes pro inflammatory cytokine production in macrophages |
| topic | macrophages ACE2 COVID-19 SARS-CoV-2 IRAK-M inflammation |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.683800/full |
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