{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:36:24Z","timestamp":1790616984741,"version":"4.1.0"},"reference-count":39,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,5,17]],"date-time":"2021-05-17T00:00:00Z","timestamp":1621209600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Research Promotion Grant from the Toho University Graduate School of Medicine","award":["No. 17-01, 20-01"],"award-info":[{"award-number":["No. 17-01, 20-01"]}]},{"name":"the Program for the Strategic Research Foundation for Private Universities","award":["S1411015"],"award-info":[{"award-number":["S1411015"]}]},{"name":"the Private University Research Branding Project from the Ministry of Education, Culture, Sports, Science, and Technology","award":["no number"],"award-info":[{"award-number":["no number"]}]},{"name":"Grants-in-Aid for Scientific Research (C)","award":["18K07166"],"award-info":[{"award-number":["18K07166"]}]},{"name":"Early-Career Scientists","award":["19K17897"],"award-info":[{"award-number":["19K17897"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>CX3C Motif Chemokine Ligand 1 (CX3CL1; fractalkine) has been implicated in the pathogenesis of rheumatoid arthritis (RA) and its inhibition was found to attenuate arthritis in mice as well as in a clinical trial. Therefore, we investigated the effects of an anti-CX3CL1 monoclonal antibody (mAb) on immune-mediated interstitial lung disease (ILD) in SKG mice, which exhibit similar pathological and clinical features to human RA-ILD. CX3CL1 and CX3C chemokine receptor 1 (CX3CR1), the receptor for CX3CL1, were both expressed in the fibroblastic foci of lung tissue and the number of bronchoalveolar fluid (BALF) cells was elevated in ILD in SKG mice. No significant changes were observed in lung fibrosis or the number of BALF cells by the treatment with anti-CX3CL1 mAb. However, significantly greater reductions were observed in the number of M1 macrophages than in M2 macrophages in the BALF of treated mice. Furthermore, CX3CR1 expression levels were significantly higher in M1 macrophages than in M2 macrophages. These results suggest the stronger inhibitory effects of the anti-CX3CL1 mAb treatment against the alveolar infiltration of M1 macrophages than M2 macrophages in ILD in SKG mice. Thus, the CX3CL1-CX3CR1 axis may be involved in the infiltration of inflammatory M1 macrophages in RA-ILD.<\/jats:p>","DOI":"10.3390\/ph14050474","type":"journal-article","created":{"date-parts":[[2021,5,17]],"date-time":"2021-05-17T12:19:57Z","timestamp":1621253997000},"page":"474","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Treatment with an Anti-CX3CL1 Antibody Suppresses M1 Macrophage Infiltration in Interstitial Lung Disease in SKG Mice"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4321-5357","authenticated-orcid":false,"given":"Satoshi","family":"Mizutani","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Division of Rheumatology, Toho University School of Medicine, Ota-ku, Tokyo 143-8541, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junko","family":"Nishio","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Rheumatology, Toho University School of Medicine, Ota-ku, Tokyo 143-8541, Japan"},{"name":"Department of Immunopathology and Immunoregulation, Toho University School of Medicine, Ota-ku, Tokyo 143-8540, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanoh","family":"Kondo","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Rheumatology, Toho University School of Medicine, Ota-ku, Tokyo 143-8541, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaori","family":"Motomura","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Rheumatology, Toho University School of Medicine, Ota-ku, Tokyo 143-8541, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zento","family":"Yamada","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Rheumatology, Toho University School of Medicine, Ota-ku, Tokyo 143-8541, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shotaro","family":"Masuoka","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Rheumatology, Toho University School of Medicine, Ota-ku, Tokyo 143-8541, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soichi","family":"Yamada","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Rheumatology, Toho University School of Medicine, Ota-ku, Tokyo 143-8541, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9853-8057","authenticated-orcid":false,"given":"Sei","family":"Muraoka","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Rheumatology, Toho University School of Medicine, Ota-ku, Tokyo 143-8541, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoto","family":"Ishii","sequence":"additional","affiliation":[{"name":"KAN Research Institute, Inc., Chuo-ku, Kobe-shi, Hyogo 650-0047, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshikazu","family":"Kuboi","sequence":"additional","affiliation":[{"name":"KAN Research Institute, Inc., Chuo-ku, Kobe-shi, Hyogo 650-0047, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sho","family":"Sendo","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Chuo-ku, Kobe-shi, Hyogo 650-0017, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetuo","family":"Mikami","sequence":"additional","affiliation":[{"name":"Department of Pathology, Toho University School of Medicine, Ota-ku, Tokyo 143-8540, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshio","family":"Imai","sequence":"additional","affiliation":[{"name":"KAN Research Institute, Inc., Chuo-ku, Kobe-shi, Hyogo 650-0047, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3482-074X","authenticated-orcid":false,"given":"Toshihiro","family":"Nanki","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Rheumatology, Toho University School of Medicine, Ota-ku, Tokyo 143-8541, 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J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1164\/rccm.201004-0622OC","article-title":"Rheumatoid arthritis-interstitial lung disease-associated mortality","volume":"183","author":"Olson","year":"2011","journal-title":"Am. J. Respir Crit. Care Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1378\/chest.13-1394","article-title":"Functional impact of a spectrum of interstitial lung abnormalities in rheumatoid arthritis","volume":"146","author":"Doyle","year":"2014","journal-title":"Chest"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1002\/path.4133","article-title":"Macrophage plasticity and polarization in tissue repair and remodelling","volume":"229","author":"Mantovani","year":"2013","journal-title":"J. Pathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.immuni.2016.02.015","article-title":"Macrophages in Tissue Repair, Regeneration, and Fibrosis","volume":"44","author":"Wynn","year":"2016","journal-title":"Immunity"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"L358","DOI":"10.1152\/ajplung.00341.2014","article-title":"Distinct macrophage phenotypes in allergic and nonallergic lung inflammation","volume":"308","author":"Robbe","year":"2015","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3858","DOI":"10.4049\/jimmunol.1302821","article-title":"CCL2 shapes macrophage polarization by GM-CSF and M-CSF: Identification of CCL2\/CCR2-dependent gene expression profile","volume":"192","author":"Nieto","year":"2014","journal-title":"J. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1016\/j.imbio.2010.05.020","article-title":"Heme Oxygenase-1 expression in M-CSF-polarized M2 macrophages contributes to LPS-induced IL-10 release","volume":"215","author":"Vega","year":"2010","journal-title":"Immunobiology"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Lu, H.L., Huang, X.Y., Luo, Y.F., Tan, W.P., Chen, P.F., and Guo, Y.B. (2018). Activation of M1 macrophages plays a critical role in the initiation of acute lung injury. Biosci. Rep., 38.","DOI":"10.1042\/BSR20171555"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"L834","DOI":"10.1152\/ajplung.00235.2017","article-title":"Metabolic characterization and RNA profiling reveal glycolytic dependence of profibrotic phenotype of alveolar macrophages in lung fibrosis","volume":"313","author":"Xie","year":"2017","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1038\/mt.2016.36","article-title":"Chop Deficiency Protects Mice Against Bleomycin-induced Pulmonary Fibrosis by Attenuating M2 Macrophage Production","volume":"24","author":"Yao","year":"2016","journal-title":"Mol. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1002\/reg2.97","article-title":"The diversity of myeloid immune cells shaping wound repair and fibrosis in the lung","volume":"5","author":"Song","year":"2018","journal-title":"Regeneration"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/S0002-9440(10)62289-4","article-title":"CCR2-mediated recruitment of fibrocytes to the alveolar space after fibrotic injury","volume":"166","author":"Moore","year":"2005","journal-title":"Am. J. Pathol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"L341","DOI":"10.1152\/ajplung.00122.2010","article-title":"New concepts of IL-10-induced lung fibrosis: Fibrocyte recruitment and M2 activation in a CCL2\/CCR2 axis","volume":"300","author":"Sun","year":"2011","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2387","DOI":"10.1084\/jem.20162152","article-title":"Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span","volume":"214","author":"Misharin","year":"2017","journal-title":"J. Exp. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1165\/rcmb.2017-0154OC","article-title":"Deletion of c-FLIP from CD11b(hi) Macrophages Prevents Development of Bleomycin-induced Lung Fibrosis","volume":"58","author":"McCubbrey","year":"2018","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e156","DOI":"10.1182\/blood-2011-04-348946","article-title":"In vivo structure\/function and expression analysis of the CX3C chemokine fractalkine","volume":"118","author":"Kim","year":"2011","journal-title":"Blood"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"37993","DOI":"10.1074\/jbc.M106434200","article-title":"Tumor necrosis factor-alpha-converting enzyme (ADAM17) mediates the cleavage and shedding of fractalkine (CX3CL1)","volume":"276","author":"Garton","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"44622","DOI":"10.1074\/jbc.M107327200","article-title":"Tumor necrosis factor-alpha-converting enzyme mediates the inducible cleavage of fractalkine","volume":"276","author":"Tsou","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6173","DOI":"10.4049\/jimmunol.168.12.6173","article-title":"Dual functions of fractalkine\/CX3C ligand 1 in trafficking of perforin+\/granzyme B+ cytotoxic effector lymphocytes that are defined by CX3CR1 expression","volume":"168","author":"Nishimura","year":"2002","journal-title":"J. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1568","DOI":"10.1002\/1529-0131(200107)44:7<1568::AID-ART280>3.0.CO;2-1","article-title":"Fractalkine, a novel chemokine in rheumatoid arthritis and in rat adjuvant-induced arthritis","volume":"44","author":"Ruth","year":"2001","journal-title":"Arthritis Rheum."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"7825","DOI":"10.4049\/jimmunol.0803627","article-title":"Role of CX3CL1\/fractalkine in osteoclast differentiation and bone resorption","volume":"183","author":"Koizumi","year":"2009","journal-title":"J. Immunol."},{"key":"ref_24","first-page":"1918","article-title":"Proinflammatory role of fractalkine (CX3CL1) in rheumatoid arthritis","volume":"30","author":"Blaschke","year":"2003","journal-title":"J. Rheumatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"7010","DOI":"10.4049\/jimmunol.173.11.7010","article-title":"Inhibition of fractalkine ameliorates murine collagen-induced arthritis","volume":"173","author":"Nanki","year":"2004","journal-title":"J. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Tanaka, Y., Takeuchi, T., Yamanaka, H., Nanki, T., Umehara, H., Yasuda, N., Tago, F., Kitahara, Y., Kawakubo, M., and Torii, K. (2020). Efficacy and Safety of E6011, an Anti-Fractalkine Monoclonal Antibody, in Patients With Active Rheumatoid Arthritis With Inadequate Response to Methotrexate: Results of a Randomized, Double-Blind, Placebo-Controlled Phase II Study. Arthritis Rheumatol.","DOI":"10.2139\/ssrn.3523879"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1080\/14397595.2017.1337056","article-title":"Safety, pharmacokinetics, and efficacy of E6011, an antifractalkine monoclonal antibody, in a first-in-patient phase 1\/2 study on rheumatoid arthritis","volume":"28","author":"Tanaka","year":"2018","journal-title":"Mod. Rheumatol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2357","DOI":"10.7150\/ijms.43748","article-title":"CX3CL1 and CX3CR1 could be a relevant molecular axis in the pathophysiology of idiopathic pulmonary fibrosis","volume":"17","author":"Herrera","year":"2020","journal-title":"Int. J. Med. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Yamada, S., Miyoshi, S., Nishio, J., Mizutani, S., Yamada, Z., Kusunoki, N., Sato, H., Kuboi, Y., Hoshino-Negishi, K., and Ishii, N. (2020). Effects of CX3CL1 inhibition on murine bleomycin-induced interstitial pneumonia. Eur. J. Inflamm., 18.","DOI":"10.1177\/2058739220959903"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"R48","DOI":"10.1186\/ar3761","article-title":"Serum level of soluble CX3CL1\/fractalkine is elevated in patients with polymyositis and dermatomyositis, which is correlated with disease activity","volume":"14","author":"Suzuki","year":"2012","journal-title":"Arthritis Res. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Hoffmann-Vold, A.M., Weigt, S.S., Palchevskiy, V., Volkmann, E., Saggar, R., Li, N., Midtvedt, O., Lund, M.B., Garen, T., and Fishbein, M.C. (2018). Augmented concentrations of CX3CL1 are associated with interstitial lung disease in systemic sclerosis. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0206545"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1038\/s41590-018-0276-y","article-title":"Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage","volume":"20","author":"Aran","year":"2019","journal-title":"Nat. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"16833","DOI":"10.1038\/s41598-017-17007-8","article-title":"Essential involvement of the CX3CL1-CX3CR1 axis in bleomycin-induced pulmonary fibrosis via regulation of fibrocyte and M2 macrophage migration","volume":"7","author":"Ishida","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1038\/nature02119","article-title":"Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice","volume":"426","author":"Sakaguchi","year":"2003","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.smim.2006.03.007","article-title":"Spontaneous development of autoimmune arthritis due to genetic anomaly of T cell signal transduction: Part 1","volume":"Volume 18","author":"Sakaguchi","year":"2006","journal-title":"Seminars in Immunology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"849","DOI":"10.4049\/jimmunol.1303255","article-title":"GM-CSF but not IL-17 is critical for the development of severe interstitial lung disease in SKG mice","volume":"193","author":"Shiomi","year":"2014","journal-title":"J. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1136\/jcp.41.4.467","article-title":"Simple method of estimating severity of pulmonary fibrosis on a numerical scale","volume":"41","author":"Ashcroft","year":"1988","journal-title":"J. Clin. Pathol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6987","DOI":"10.4049\/jimmunol.175.10.6987","article-title":"Inhibition of CX3CL1 (fractalkine) improves experimental autoimmune myositis in SJL\/J mice","volume":"175","author":"Suzuki","year":"2005","journal-title":"J. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1002\/art.40688","article-title":"Role of Anti-Fractalkine Antibody in Suppression of Joint Destruction by Inhibiting Migration of Osteoclast Precursors to the Synovium in Experimental Arthritis","volume":"71","author":"Ohkuro","year":"2019","journal-title":"Arthritis Rheumatol."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/14\/5\/474\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:02:50Z","timestamp":1760162570000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/14\/5\/474"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,17]]},"references-count":39,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["ph14050474"],"URL":"https:\/\/doi.org\/10.3390\/ph14050474","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,17]]}}}