TREM-1-Linked Inflammatory Cargo in SARS-CoV-2-Stimulated Macrophage Extracellular Vesicles Drives Cellular Senescence and Impairs Antibacterial Defense

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da Silva-Neto, Pedro V. ; de Carvalho, Jonatan C. S. ; Toro, Diana M. ; Oliveira, Bianca T. M. ; Cominal, Jucara G. ; Castro, Ricardo C. ; Almeida, Maria A. ; Prado, Cibele M. ; Arruda, Eurico ; Frantz, Fabiani G. ; Ramos, Ana P. ; Ciancaglini, Pietro ; Martins, Ronaldo B. ; da Silveira, Juliano C. ; Almeida, Fausto ; Malmegrim, Kelen C. R. ; Sorgi, Carlos A.

• Document type: Journal article
• Source: Viruses-Basel; v. 17, n. 5, p. 20-pg., 2025-04-24.

Abstract

The COVID-19 pandemic, caused by SARS-CoV-2, has significantly affected global health, with severe inflammatory responses leading to tissue damage and persistent symptoms. Macrophage-derived extracellular vesicles (EVs) are involved in the modulation of immune responses, but their involvement in SARS-CoV-2-induced inflammation and senescence remains unclear. Triggering receptors expressed on myeloid cell-1 (TREM-1) are myeloid cell receptors that amplify inflammation, described as a biomarker of the severity and mortality of COVID-19. This study investigated the composition and effects of macrophage-derived EVs stimulated by SARS-CoV-2 (M phi V-EVs) on the recipient cell response. Our results, for the first time, show that SARS-CoV-2 stimulation modifies the cargo profile of M phi V-EVs, enriching them with TREM-1 and miRNA-155 association, along with MMP-9 and IL-8/CXCL8. These EVs carry senescence-associated secretory phenotype (SASP) components, promote cellular senescence, and compromise antibacterial defenses upon internalization. Our findings provide evidence that M phi V-EVs are key drivers of inflammation and immune dysfunction, underscoring their potential as therapeutic targets in COVID-19. (AU)

• FAPESP's process: 23/07776-6 - Evaluation of the therapeutic role of selective serotonin reuptake inhibitor antidepressants in modulating the inflammatory response and sphingolipid metabolism in SARS-CoV-2 infected macrophages
• Grantee: Jonatan Constança Silva de Carvalho
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 24/03414-5 - Integrated Analysis of Sphingolipid Metabolism and Extracellular Particle Composition in the Context of a Hight-Fat-Diet: Implications for Lipoproteins, Vesicle Biogenesis, and the Role in Macrophage Response to COVID-19
• Grantee: Carlos Arterio Sorgi
• Support Opportunities: Regular Research Grants
• FAPESP's process: 21/04590-3 - Exploratory analysis of functional lipidomics in the COVID-19 pathophysiology: molecular targets, metabolism and biochemical reprogramming due to hypoxia
• Grantee: Carlos Arterio Sorgi
• Support Opportunities: Regular Research Grants
• FAPESP's process: 22/07287-2 - Characterization and immunomodulatory potential of extracellular vesicles from macrophages stimulated with SARS-CoV-2 particles
• Grantee: Jonatan Constança Silva de Carvalho
• Support Opportunities: Scholarships in Brazil - Scientific Initiation