Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 50, Pages E11721-E11730Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1811432115
Keywords
apoptotic exosome-like vesicles; sphingosine-1-phosphate; sphingosine-1-phosphate receptors; damage-associated molecular patterns; IL-1 beta
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Funding
- Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education [NRF-2018R1D1A1B07048257, NRF-2017R1D1A1B03034312, NRF-2016R1D1A1B03934488, NRF-2013R1A2A2A01008507]
- Korea Health Technology Research and Development Project through the Korea Health Industry Development Institute - Ministry of Health and Welfare of the Republic of Korea [HI16C0992]
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Recent research has led to contradictory notions regarding the conventional theory that apoptotic cell death can evoke inflammatory or immunogenic responses orchestrated by released damage-associated patterns (DAMPs). By inducing IL-1 beta from bone marrow-derived macrophages in an effort to determine the inflammatory mediators released from apoptotic cells, we found that exosomal fractions called apoptotic exosome-like vesicles (AEVs) prepared from apoptotic-conditioned medium were the main inflammatory factors. These AEVs showed characteristics of exosomes in their size, density, morphology, and protein expression but had unique marker proteins, sphingosine-1-phosphate receptors 1 and 3 (S1PR1 and 3). Their biogenesis was completely dependent on cellular sphingosine-1-phosphate (S1P)/S1PRs signaling from multiple fine spindles of plasma membrane accompanied by F-actin, S1PR1, S1PR3, and CD63 at the early apoptotic phase and progressing to the maturation of F-actin-guided multivesicular endosomes mediated by G beta gamma subunits of S1PRs downstream. S1P-loaded S1PRs on AEVs were critical factors for inducing IL-1 beta via NF-kappa B transcriptional factor and p38 MAPK, possibly through the RHOA/NOD2 axis, in differentiating macrophages. The AEVs induced genes of proinflammatory cytokines, chemokines, and mediators in both in vitro and in vivo models. In conclusion, AEVs could be key inflammatory mediators, acting as DAMPs that could explain the pathogeneses of various chronic inflammations, autoimmune diseases, or cancers in the future.
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