{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T19:58:41Z","timestamp":1779134321256,"version":"3.51.4"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2013,8,1]],"date-time":"2013-08-01T00:00:00Z","timestamp":1375315200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Fractalkine, a chemokine anchored to neurons or peripheral endothelial cells, serves as an adhesion molecule or as a soluble chemoattractant. Fractalkine binds CX3CR1 on microglia and circulating monocytes, dendritic cells, and NK cells. The aim of this study is to determine the role of CX3CR1 in the trafficking and function of myeloid cells to the CNS during experimental autoimmune encephalomyelitis (EAE). Our results show that, in models of active EAE, Cx3cr1\u2212\/\u2212 mice exhibited more severe neurologic deficiencies. Bone marrow chimeric mice confirmed that CX3CR1 deficiency in bone marrow enhanced EAE severity. Notably, CX3CR1 deficiency was associated with an increased accumulation of CD115+Ly6C\u2212CD11c+ dendritic cells into EAE-affected brains that correlated with enhanced demyelination and neuronal damage. Furthermore, higher IFN-\u03b3 and IL-17 levels were detected in cerebellar and spinal cord tissues of CX3CR1-deficient mice. Analyses of peripheral responses during disease initiation revealed a higher frequency of IFN-\u03b3\u2013 and IL-17\u2013producing T cells in lymphoid tissues of CX3CR1-deficient as well as enhanced T cell proliferation induced by CX3CR1-deficient dendritic cells. In addition, adoptive transfer of myelin oligodendrocyte glycoprotein35\u201355-reactive wild-type T cells induced substantially more severe EAE in CX3CR1-deficient recipients when compared with wild-type recipients. Collectively, the data demonstrate that besides its role in chemoattraction, CX3CR1 is a key regulator of myeloid cell activation contributing to the establishment of adaptive immune responses.<\/jats:p>","DOI":"10.4049\/jimmunol.1300040","type":"journal-article","created":{"date-parts":[[2013,7,2]],"date-time":"2013-07-02T04:41:43Z","timestamp":1372740103000},"page":"1063-1072","source":"Crossref","is-referenced-by-count":72,"title":["Regulation of Adaptive Immunity by the Fractalkine Receptor during Autoimmune Inflammation"],"prefix":"10.1093","volume":"191","author":[{"given":"Jenny A","family":"Garcia","sequence":"first","affiliation":[{"name":"Department of Biology, University of Texas at San Antonio , San Antonio, TX 78249"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paula A","family":"Pino","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Texas at San Antonio , San Antonio, TX 78249"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Makiko","family":"Mizutani","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Neuroinflammation Research Center, Lerner Research Institute, Cleveland Clinic , Cleveland, OH 44195"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra M","family":"Cardona","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Texas at San Antonio , San Antonio, TX 78249"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Israel F","family":"Charo","sequence":"additional","affiliation":[{"name":"Gladstone Institute of Cardiovascular Research , San Francisco, CA 94158"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard M","family":"Ransohoff","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Neuroinflammation Research Center, Lerner Research Institute, Cleveland Clinic , Cleveland, OH 44195"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas G","family":"Forsthuber","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Texas at San Antonio , San Antonio, TX 78249"},{"name":"South Texas Center for Emerging Infectious Diseases, University of Texas at San Antonio , San Antonio, TX 78249"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Astrid E","family":"Cardona","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Texas at San Antonio , San Antonio, TX 78249"},{"name":"South Texas Center for Emerging Infectious Diseases, University of Texas at San Antonio , San Antonio, TX 78249"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2013,8,1]]},"reference":[{"key":"2025032405143965600_r1","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1182\/blood-2007-10-118497","article-title":"Scavenging roles of chemokine receptors: chemokine receptor deficiency is associated with increased levels of ligand in circulation and tissues","volume":"112","author":"Cardona","year":"2008","journal-title":"Blood"},{"key":"2025032405143965600_r2","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1038\/nn1715","article-title":"Control of microglial neurotoxicity by the fractalkine receptor","volume":"9","author":"Cardona","year":"2006","journal-title":"Nat. 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Blood Flow Metab."},{"key":"2025032405143965600_r36","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1097\/MEG.0b013e3282f824c9","article-title":"The V249I polymorphism of the CX3CR1 gene is associated with fibrostenotic disease behavior in patients with Crohn\u2019s disease","volume":"20","author":"Sabate","year":"2008","journal-title":"Eur. J. Gastroenterol. Hepatol."},{"key":"2025032405143965600_r37","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1161\/hh1701.095642","article-title":"Association between polymorphism in the chemokine receptor CX3CR1 and coronary vascular endothelial dysfunction and atherosclerosis","volume":"89","author":"McDermott","year":"2001","journal-title":"Circ. 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Immunol."},{"key":"2025032405143965600_r43","doi-asserted-by":"crossref","first-page":"7054","DOI":"10.4049\/jimmunol.169.12.7054","article-title":"Interactions between hemopoietically derived TNF and central nervous system-resident glial chemokines underlie initiation of autoimmune inflammation in the brain","volume":"169","author":"Murphy","year":"2002","journal-title":"J. Immunol."},{"key":"2025032405143965600_r44","doi-asserted-by":"crossref","first-page":"944","DOI":"10.4049\/jimmunol.154.2.944","article-title":"TNF-alpha expression by resident microglia and infiltrating leukocytes in the central nervous system of mice with experimental allergic encephalomyelitis: regulation by Th1 cytokines","volume":"154","author":"Renno","year":"1995","journal-title":"J. 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