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We recently revealed the important role of intracardiac EVs induced by myocardial ischemia\/reperfusion on cardiac injury and dysfunction. However, the role of EVs isolated from normal tissues remains unclear. Here we found that EVs, derived from murine heart, lung, liver and kidney have similar effects on macrophages and regulate the inflammation, chemotaxis, and phagocytosis of macrophages. Interestingly, EV\u2010treated macrophages showed LPS resistance with reduced expressions of inflammatory cytokines and enhanced phagocytic activity. Furthermore, we demonstrated that the protein content in EVs contributed to the activation of inflammation, while the RNA component mainly limited the excessive inflammatory response of macrophages to LPS. The enrichment of miRNAs, including miR\u2010148a\u20103p, miR\u20101a\u20103p and miR\u2010143\u20103p was confirmed in tissue EVs. These EV\u2010enriched miRNAs contributed to the inflammation remission in LPS induced macrophages through multiple pathways, including STAT3, P65 and SAPK\/JNK. Moreover, administration of both EVs and EV\u2010educated macrophages attenuated septic injury and cytokine storm in murine CLP models. Taken together, the present study disclosed that EVs from normal tissues can orchestrate the homeostasis of macrophages and attenuate inflammatory injury of sepsis. Therefore, tissue derived EVs or their derivatives may serve as potential therapeutic strategies in inflammatory diseases.<\/jats:p>","DOI":"10.1002\/btm2.10609","type":"journal-article","created":{"date-parts":[[2023,10,14]],"date-time":"2023-10-14T06:36:28Z","timestamp":1697265388000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Extracellular vesicles from normal tissues orchestrate the homeostasis of macrophages and attenuate inflammatory injury of sepsis"],"prefix":"10.1002","volume":"9","author":[{"given":"Xinyu","family":"Ge","sequence":"first","affiliation":[{"name":"Research Center for Translational Medicine, Shanghai East Hospital Tongji University School of Medicine  Shanghai China"},{"name":"Shanghai Heart Failure Research Center, Shanghai East Hospital Tongji University School of Medicine  Shanghai China"},{"name":"Department of thoracic Surgery, Shanghai East Hospital Tongji University School of 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