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The specific mechanisms are still not completely defined. The aim of this study was to investigate the ability of HAF-EVs, isolated from pregnant women who underwent amniocentesis and purified by gradient ultracentrifugation, to affect inflammasome activation in the human monocytes. Proteomic studies revealed that HAF-EV samples expressed several immunoregulatory molecules as well as small amounts of endotoxin. Surprisingly, metagenomic analysis shows the presence of specific bacterial strain variants associated with HAF-EVs as potential sources of the endotoxin. Remarkably, we showed that a single treatment of THP-1 cells with HAF-EVs triggered inflammasome activation, whereas the same treatment followed by LPS and ATP sensitization prevented inflammasome activation, a pathway resembling monocyte refractories. A bioinformatics analysis of microbiota-HAF-EVs functional pathways confirmed the presence of enzymes for endotoxin biosynthesis as well as others associated with immunoregulatory functions. Overall, these data suggest that HAF-EVs could serve as a source of the isolation of a specific microbiota during early pregnancy. Moreover, HAF-EVs could act as a novel system to balance immune training and tolerance by modulating the inflammasome in monocytes or other cells.<\/jats:p>","DOI":"10.3390\/ijms24032527","type":"journal-article","created":{"date-parts":[[2023,1,30]],"date-time":"2023-01-30T04:58:25Z","timestamp":1675054705000},"page":"2527","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Microbiota-Associated HAF-EVs Regulate Monocytes by Triggering or Inhibiting Inflammasome Activation"],"prefix":"10.3390","volume":"24","author":[{"given":"Emilia","family":"Nunzi","sequence":"first","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, Polo Unico Sant\u2019Andrea delle Fratte, P.e Lucio Severi 1, 06132 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6159-0927","authenticated-orcid":false,"given":"Letizia","family":"Mezzasoma","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, Polo Unico Sant\u2019Andrea delle Fratte, P.e Lucio Severi 1, 06132 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8106-1600","authenticated-orcid":false,"given":"Ilaria","family":"Bellezza","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, Polo Unico Sant\u2019Andrea delle Fratte, P.e Lucio Severi 1, 06132 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7071-0302","authenticated-orcid":false,"given":"Teresa","family":"Zelante","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of 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