Extracellular vesicles from primary human macrophages stimulated with VIP or PACAP mediate anti-SARS-CoV-2 activities in monocytes through NF-κB signaling pathway

Microbes Infect. 2024 Nov-Dec;26(8):105400. doi: 10.1016/j.micinf.2024.105400. Epub 2024 Jul 26.

Abstract

Infection by SARS-CoV-2 is associated with uncontrolled inflammatory response during COVID-19 severe disease, in which monocytes are one of the main sources of pro-inflammatory mediators leading to acute respiratory distress syndrome. Extracellular vesicles (EVs) from different cells play important roles during SARS-CoV-2 infection, but investigations describing the involvement of EVs from primary human monocyte-derived macrophages (MDM) on the regulation of this infection are not available. Here, we describe the effects of EVs released by MDM stimulated with the neuropeptides VIP and PACAP on SARS-CoV-2-infected monocytes. MDM-derived EVs were isolated by differential centrifugation of medium collected from cells cultured for 24 h in serum-reduced conditions. Based on morphological properties, we distinguished two subpopulations of MDM-EVs, namely large (LEV) and small EVs (SEV). We found that MDM-derived EVs stimulated with the neuropeptides inhibited SARS-CoV-2 RNA synthesis/replication in monocytes, protected these cells from virus-induced cytopathic effects and reduced the production of pro-inflammatory mediators. In addition, EVs derived from VIP- and PACAP-treated MDM prevented the SARS-CoV-2-induced NF-κB activation. Overall, our findings suggest that MDM-EVs are endowed with immunoregulatory properties that might contribute to the antiviral and anti-inflammatory responses in SARS-CoV-2-infected monocytes and expand our knowledge of EV effects during COVID-19 pathogenesis.

Keywords: Extracellular vesicles; Macrophages; Monocytes; PACAP; SARS-CoV-2; VIP.

MeSH terms

  • COVID-19* / immunology
  • COVID-19* / metabolism
  • COVID-19* / virology
  • Cells, Cultured
  • Extracellular Vesicles* / immunology
  • Extracellular Vesicles* / metabolism
  • Extracellular Vesicles* / virology
  • Humans
  • Macrophages* / immunology
  • Macrophages* / metabolism
  • Macrophages* / virology
  • Monocytes* / immunology
  • Monocytes* / metabolism
  • Monocytes* / virology
  • NF-kappa B* / metabolism
  • Pituitary Adenylate Cyclase-Activating Polypeptide* / metabolism
  • Pituitary Adenylate Cyclase-Activating Polypeptide* / pharmacology
  • SARS-CoV-2* / immunology
  • Signal Transduction*
  • Vasoactive Intestinal Peptide* / metabolism
  • Vasoactive Intestinal Peptide* / pharmacology
  • Virus Replication / drug effects

Substances

  • NF-kappa B
  • Vasoactive Intestinal Peptide
  • Pituitary Adenylate Cyclase-Activating Polypeptide