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The precise roles of CX<jats:sub>3<\/jats:sub>CR1 in the liver have been investigated but not clearly elucidated. Here, we investigated the roles of CX<jats:sub>3<\/jats:sub>CR1 in hepatic macrophages and liver injury. Hepatic and splenic CX<jats:sub>3<\/jats:sub>CR1<jats:sup>low<\/jats:sup>F4\/80<jats:sup>low<\/jats:sup> monocytes and CX<jats:sub>3<\/jats:sub>CR1<jats:sup>low<\/jats:sup>CD16<jats:sup>\u2212<\/jats:sup> monocytes were differentiated into CX<jats:sub>3<\/jats:sub>CR1<jats:sup>high<\/jats:sup>F4\/80<jats:sup>high<\/jats:sup> or CX<jats:sub>3<\/jats:sub>CR1<jats:sup>high<\/jats:sup>CD16<jats:sup>+<\/jats:sup> macrophages by co-culture with endothelial cells. Moreover, CX<jats:sub>3<\/jats:sub>CL1 deficiency in human umbilical vein endothelial cells (HUVECs) attenuated the expression of interleukin-1\u03b2 (IL-1\u03b2) and tumor necrosis factor-\u03b1 (TNF-\u03b1), whereas recombinant CX<jats:sub>3<\/jats:sub>CL1 treatment reversed this expression in co-cultured monocytes. Upon treatment with clodronate liposome, hepatic F4\/80<jats:sup>high<\/jats:sup> macrophages were successfully depleted at day 2 and recovered similarly in CX<jats:sub>3<\/jats:sub>CR1<jats:sup>+\/GFP<\/jats:sup> and CX<jats:sub>3<\/jats:sub>CR1<jats:sup>GFP\/GFP<\/jats:sup> mice at week 4, suggesting a CX<jats:sub>3<\/jats:sub>CR1-independent replacement. However, F4\/80<jats:sup>high<\/jats:sup> macrophages of CX<jats:sub>3<\/jats:sub>CR1<jats:sup>+\/GFP<\/jats:sup> showed a stronger pro-inflammatory phenotype than CX<jats:sub>3<\/jats:sub>CR1<jats:sup>GFP\/GFP<\/jats:sup> mice. In clodronate-treated chimeric CX<jats:sub>3<\/jats:sub>CR1<jats:sup>+\/GFP<\/jats:sup> and CX<jats:sub>3<\/jats:sub>CR1<jats:sup>GFP\/GFP<\/jats:sup> mice, CX<jats:sub>3<\/jats:sub>CR1<jats:sup>+<\/jats:sup>F4\/80<jats:sup>high<\/jats:sup> macrophages showed higher expression of IL-1\u03b2 and TNF-\u03b1 than CX<jats:sub>3<\/jats:sub>CR1<jats:sup>\u2212<\/jats:sup>F4\/80<jats:sup>high<\/jats:sup> macrophages. In alcoholic liver injury, despite the similar frequency of hepatic F4\/80<jats:sup>high<\/jats:sup> macrophages, CX<jats:sub>3<\/jats:sub>CR1<jats:sup>GFP\/GFP<\/jats:sup> mice showed reduced liver injury, hepatic fat accumulation, and inflammatory responses than CX<jats:sub>3<\/jats:sub>CR1<jats:sup>+\/GFP<\/jats:sup> mice. Thus, CX<jats:sub>3<\/jats:sub>CR1 could be a novel therapeutic target for pro-inflammatory macrophage-mediated liver injury.<\/jats:p>","DOI":"10.1038\/s41598-018-33440-9","type":"journal-article","created":{"date-parts":[[2018,10,4]],"date-time":"2018-10-04T11:00:52Z","timestamp":1538650852000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["CX3CR1 differentiates F4\/80low monocytes into pro-inflammatory F4\/80high macrophages in the liver"],"prefix":"10.1038","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6396-0859","authenticated-orcid":false,"given":"Young-Sun","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myung-Ho","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyon-Seung","family":"Yi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1319-6164","authenticated-orcid":false,"given":"So Yeon","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hee-Hoon","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3924-0434","authenticated-orcid":false,"given":"Ji Hoon","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong Eun","family":"Yeon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwan Soo","family":"Byun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Seok","family":"Byun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Won-Il","family":"Jeong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,10,10]]},"reference":[{"key":"33440_CR1","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1002\/hep.22034","volume":"47","author":"B Gao","year":"2008","unstructured":"Gao, B., Jeong, W. 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