Molecular mechanisms of biogenesis of apoptotic exosome-like vesicles and their roles as damage-associated molecular...

Area of Science:

• Cell Biology
• Immunology
• Molecular Biology

Background:

• Conventional theories suggest apoptotic cell death can trigger inflammatory responses via damage-associated molecular patterns (DAMPs).
• Recent research presents conflicting findings on the inflammatory potential of apoptotic cells.
• Identifying specific mediators released during apoptosis is crucial for understanding inflammatory processes.

Purpose of the Study:

• To identify the primary inflammatory mediators released from apoptotic cells.
• To investigate the role of exosome-like vesicles in initiating inflammatory responses.
• To elucidate the biogenesis and inflammatory mechanisms of these novel vesicles.

Main Methods:

• Induction of IL-1β in bone marrow-derived macrophages.
• Isolation and characterization of "apoptotic exosome-like vesicles" (AEVs) from apoptotic-conditioned medium.
• Analysis of AEVs' size, density, morphology, protein expression, and unique markers (S1PR1, S1PR3).
• Investigation of AEV biogenesis pathway involving sphingosine-1-phosphate (S1P)/S1PRs signaling and F-actin.
• Assessment of AEVs' capacity to induce inflammatory gene expression in vitro and in vivo.

Main Results:

• AEVs were identified as the main inflammatory factors released from apoptotic cells.
• AEVs share exosome characteristics but possess unique markers S1PR1 and S1PR3.
• AEV biogenesis depends on cellular S1P/S1PRs signaling, F-actin, and Gβγ subunits.
• S1P-loaded S1PRs on AEVs critically induce IL-1β via NF-κB and p38 MAPK pathways.
• AEVs induced proinflammatory genes in both in vitro and in vivo models.

Conclusions:

• AEVs are key inflammatory mediators and novel DAMPs.
• AEVs provide a potential explanation for the pathogenesis of chronic inflammation, autoimmune diseases, and cancers.
• Further research into AEVs could lead to new therapeutic strategies for inflammatory conditions.