{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T14:59:01Z","timestamp":1792249141200,"version":"4.4.0"},"reference-count":0,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T00:00:00Z","timestamp":1779321600000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["NO. 82302021"],"award-info":[{"award-number":["NO. 82302021"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Inflammation"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Methotrexate (MTX) is the first-line treatment for rheumatoid arthritis (RA), but patient responses are highly variable. Macrophages are central drivers of RA inflammation, yet how monocyte\/macrophage heterogeneity and transcriptional programs influence MTX responsiveness remains unclear. Single-cell RNA sequencing was performed on peripheral blood mononuclear cells from MTX-responsive and MTX-unresponsive RA patients to define immune composition and macrophage-like monocyte subsets. Polarization states were assessed using gene-signature scoring and pseudotime analysis. The role of inhibitor of differentiation 2 (ID2) was examined in LPS-stimulated RA patient\u2013derived macrophages using gain- and loss-of-function approaches, cytokine assays and chromatin immunoprecipitation assays. Although overall immune cell distributions were similar between groups, macrophage-like monocytes from MTX-unresponsive patients exhibited higher M1 polarization scores. PLBD1\u207a and CDKN1A\u207a macrophage-like monocytes were enriched in MTX-unresponsive patients, whereas RLIM\u207a macrophage-like monocytes were reduced. Integrative analyses identified ID2 as a regulator associated with MTX resistance. ID2 expression was elevated in macrophage-like monocytes from MTX-unresponsive patients and positively correlated with M1 polarization. In vitro, MTX suppressed ID2 expression and inflammatory activation. ID2 knockdown reduced pro-inflammatory responses, whereas overexpression attenuated the inhibitory effects of MTX. ID2 was found to regulate EEF1A1 transcription. ID2 promotes pro-inflammatory macrophage polarization and may contribute to MTX resistance in RA.<\/jats:p>","DOI":"10.1007\/s10753-026-02527-1","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T07:34:37Z","timestamp":1779435277000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["ID2 Regulates Macrophage Polarization and Mediates Methotrexate Responsiveness in Rheumatoid Arthritis"],"prefix":"10.1007","author":[{"given":"Lu","family":"Ye","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaxiang","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weihong","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,22]]},"container-title":["Inflammation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10753-026-02527-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T07:34:37Z","timestamp":1779435277000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10753-026-02527-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,22]]},"references-count":0,"alternative-id":["2527"],"URL":"https:\/\/doi.org\/10.1007\/s10753-026-02527-1","relation":{},"ISSN":["1573-2576"],"issn-type":[{"value":"1573-2576","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,22]]},"assertion":[{"value":"10 February 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 May 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 May 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 May 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Clinical Trial Number"}},{"value":"This study was approved by the Ethics Committee of the Second Affiliated Hospital of Zhejiang University School of Medicine (approval number: 2025\u2009\u2212\u20091599). Written informed consent was obtained from all participants prior to enrollment. All procedures involving human participants were conducted in accordance with the ethical standards of the institutional research committee and the Declaration of Helsinki.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Committee Approval"}},{"value":"Written informed consent was obtained from the participants.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to Participate"}},{"value":"Not applicable.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to Publish"}},{"value":"The authors declare no competing interests.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}