{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T14:59:28Z","timestamp":1792594768860,"version":"4.5.0"},"reference-count":39,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2022,4,10]],"date-time":"2022-04-10T00:00:00Z","timestamp":1649548800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","award":["20H00553"],"award-info":[{"award-number":["20H00553"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","award":["21H03141"],"award-info":[{"award-number":["21H03141"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003478","name":"Ministry of Health, Labour and Welfare","doi-asserted-by":"publisher","award":["JPMH20FC1040"],"award-info":[{"award-number":["JPMH20FC1040"]}],"id":[{"id":"10.13039\/501100003478","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>IgG4\u2010related disease (IgG4\u2010RD) is a fibro\u2010inflammatory condition that can affect multiple organs. We previously demonstrated that <jats:italic>TLR7<\/jats:italic>\u2010transgenic C57BL\/6 mice showed elevated serum IgG1 levels and inflammation with fibrosis in the salivary glands (SGs), lungs, and pancreas. Moreover, we observed extensive Toll\u2010like receptor 7 (TLR\u20107)\u2013positive CD163+ M2 macrophage infiltration in SGs from IgG4\u2010RD patients. We undertook this study to examine the fibrotic mechanism via the TLR\u20107 pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Gene expression in SGs from human <jats:italic>TLR7<\/jats:italic>\u2010transgenic mice and IgG4\u2010RD patients was analyzed using DNA microarrays. We extracted the common up\u2010regulated TLR\u20107\u2013related genes in SGs from <jats:italic>TLR7<\/jats:italic>\u2010transgenic mice and IgG4\u2010RD patients. Finally, we investigated the interaction between CD163+ M2 macrophages and fibroblasts before and after stimulation with the TLR\u20107 agonist loxoribine.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In <jats:italic>TLR7<\/jats:italic>\u2010transgenic mice and IgG4\u2010RD patients, <jats:italic>IRAK3<\/jats:italic> and <jats:italic>IRAK4<\/jats:italic> were significantly overexpressed. Real\u2010time polymerase chain reaction validated the up\u2010regulation of only <jats:italic>IRAK4<\/jats:italic> in IgG4\u2010RD patients compared with the other groups (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05). Interleukin\u20101 receptor\u2013associated kinase 4 (IRAK4) was strongly detected in and around germinal centers in SGs from patients with IgG4\u2010related dacryoadenitis and sialadenitis alone. Double immunofluorescence staining showed that IRAK4\u2010positive cells were mainly colocalized with CD163+ M2 macrophages in SGs (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05). After stimulation with loxoribine, CD163+ M2 macrophages exhibited significantly enhanced expression of IRAK4 and NF\u2010\u03baB and increased supernatant concentrations of fibrotic cytokines. Finally, we confirmed that the number of fibroblasts was increased by culture with the supernatant of CD163+ M2 macrophages following stimulation with loxoribine (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>CD163+ M2 macrophages promote fibrosis in IgG4\u2010RD by increasing the production of fibrotic cytokines via TLR\u20107\/IRAK4\/NF\u2010\u03baB signaling.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42043","type":"journal-article","created":{"date-parts":[[2021,12,15]],"date-time":"2021-12-15T04:11:01Z","timestamp":1639541461000},"page":"892-901","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["<scp>CD163<\/scp>+ <scp>M2<\/scp> Macrophages Promote Fibrosis in <scp>IgG4\u2010Related<\/scp> Disease Via <scp>Toll\u2010like<\/scp> Receptor 7\/Interleukin\u20101 Receptor\u2013Associated Kinase 4\/<scp>NF\u2010\u03baB<\/scp> Signaling"],"prefix":"10.1002","volume":"74","author":[{"given":"Akira","family":"Chinju","sequence":"first","affiliation":[{"name":"Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2911-2244","authenticated-orcid":false,"given":"Masafumi","family":"Moriyama","sequence":"additional","affiliation":[{"name":"Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriko","family":"Kakizoe\u2010Ishiguro","sequence":"additional","affiliation":[{"name":"Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hu","family":"Chen","sequence":"additional","affiliation":[{"name":"Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuka","family":"Miyahara","sequence":"additional","affiliation":[{"name":"Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. S. M. Rafiul","family":"Haque","sequence":"additional","affiliation":[{"name":"Udayan Dental College  Rajpara Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsuhiro","family":"Furusho","sequence":"additional","affiliation":[{"name":"National Center for Geriatrics and Gerontology  Aichi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mizuki","family":"Sakamoto","sequence":"additional","affiliation":[{"name":"Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuki","family":"Kai","sequence":"additional","affiliation":[{"name":"Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kotono","family":"Kibe","sequence":"additional","affiliation":[{"name":"Kyushu University, Fukuoka, Japan and University of Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachiko","family":"Hatakeyama\u2010Furukawa","sequence":"additional","affiliation":[{"name":"Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miho","family":"Ito\u2010Ohta","sequence":"additional","affiliation":[{"name":"Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Maehara","sequence":"additional","affiliation":[{"name":"Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seiji","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,4,10]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200103083441005"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.3109\/s10165-011-0508-6"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1104650"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/BOR.0b013e3283412fd4"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.33320"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2012-201477"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2016-209139"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar3924"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.21697"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2013.07.007"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.39209"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2014.03.034"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1080\/14397595.2019.1621475"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00535-018-1440-8"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0126582"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2014.10.008"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep42413"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00535-017-1390-6"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1080\/14397595.2018.1536364"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.33386"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00535-014-0977-4"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.41052"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijom.2014.06.014"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1080\/14397595.2020.1859710"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.091153"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.3109\/s10165-004-0338-x"},{"key":"e_1_2_7_28_1","first-page":"35","article-title":"and the International Sj\u00f6gren's Syndrome Criteria Working Group. 2016 American College of Rheumatology\/European League Against Rheumatism classification criteria for primary Sj\u00f6gren's syndrome: a consensus and data\u2010driven methodology involving three international patient cohorts. 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