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In addition to the antiparasitic effect, accumulating evidence shows that artemisinins can alleviate neuroinflammatory responses in the central nervous system (CNS). However, the precise mechanisms underlying their anti\u2010neuroinflammatory effects are unclear. Herein we attempted to delineate the molecule target of artemisinin in microglia. In vitro protein intrinsic fluorescence titrations and saturation transfer difference (STD)\u2010NMR showed the direct binding of artemisinin to Toll\u2010like receptor TLR4 co\u2010receptor MD2. Cellular thermal shift assay (CETSA) showed that artemisinin binding increased MD2 stability, which implies that artemisinin directly binds to MD2 in the cellular context. Artemisinin bound MD2 showed much less collapse during the molecular dynamic simulations, which supports the increased stability of MD2 upon artemisinin binding. Flow cytometry analysis showed artemisinin inhibited LPS\u2010induced TLR4 dimerization and endocytosis in microglial BV\u20102 cells. Therefore, artemisinin was found to inhibit the TLR4\u2010JNK signaling axis and block LPS\u2010induced pro\u2010inflammatory factors nitric oxide, IL\u20101\u03b2 and TNF\u2010\u03b1 in BV\u20102 cells. Furthermore, artemisinin restored LPS\u2010induced decrease of junction proteins ZO\u20101, Occludin and Claudin\u20105 in primary brain microvessel endothelial cells, and attenuated LPS\u2010induced blood\u2013brain barrier disruption in mice as assessed by Evans blue. In all, this study unambiguously adds MD2 as a direct binding target of artemisinin in its anti\u2010neuroinflammatory function. The results also suggest that artemisinin could be repurposed as a potential therapeutic intervention for inflammatory CNS diseases.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15302-fig-0008-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.15302","type":"journal-article","created":{"date-parts":[[2021,1,16]],"date-time":"2021-01-16T21:41:32Z","timestamp":1610833292000},"page":"611-623","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Artemisinin inhibits TLR4 signaling by targeting co\u2010receptor MD2 in microglial BV\u20102 cells and prevents lipopolysaccharide\u2010induced blood\u2013brain barrier 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