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Puja Kumari, Swathy Vasudevan, Ashley Russo, Skylar Wright, Víctor Fraile-Ágreda, Dylan Krajewski, Evan Jellison, Ignacio Rubio, Michael Bauer, Atsushi Shimoyama, Koichi Fukase, Yuanpeng Zhang, Joel Pachter, Sivapriya Kailasan Vanaja, Vijay Rathinam, Unveiling the immune surveillance role of extracellular vesicles, The Journal of Immunology, Volume 212, Issue 1_Supplement, May 2024, Page 0175_5782, https://doi.org/10.4049/jimmunol.212.supp.0175.5782
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Abstract
Intracellular immune surveillance for systemic microbial components during homeostasis and infections governs host physiology and immunity. However, a long-standing question is how circulating microbial ligands become accessible to intracellular receptors. Here, we show a role for host-derived extracellular vesicles (EVs) in this process; human and murine plasma- and cell culture-derived EVs have an intrinsic capacity to bind bacterial lipopolysaccharide (LPS). Remarkably, circulating host EVs capture blood-borne LPS in vivo, and the LPS-laden EVs confer cytosolic access for LPS, triggering noncanonical inflammasome activation of GSDMD and pyroptosis. Mechanistically, the interaction between EV lipid bilayer and LPS’ lipid A underlies EV capture of LPS. Furthermore, the intracellular transfer of LPS by EVs is mediated by CD14-dependent receptor-mediated endocytosis. Overall, this study demonstrates that EVs capture and escort systemic LPS to the cytosol licensing inflammasome responses, uncovering EVs as a previously unrecognized link between systemic pathogen-associated molecular pattern (PAMPs) and intracellular immune surveillance.