{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T14:21:34Z","timestamp":1790605294435,"version":"4.1.0"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T00:00:00Z","timestamp":1736467200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p><jats:italic>IGFBP5<\/jats:italic> is a differentially expressed gene (DEG) between M1 and M2 macrophages. This study explained why it causes opposite effects in different circumstances.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Gene expression profiles of various cell subsets were compared by mining a public database. THP-1 cells were treated by siRNAs, recombinant IGFBP5, lipopolysaccharide (LPS), picropodophyllin, IGF1 or the combinations. Clinical implication of IGFBP5 changes was investigated using rheumatoid arthritis (RA) and acute lung injury (ALI) models. IGFBP5-bound and differential proteins were identified by Liquid Chromatography Mass Spectrometry method.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>IGFBP5 situated in the center of a network constructed by the DEGs of M0 and M1\/2 macrophages. Its expression negatively correlated to inflammation <jats:italic>in vitro<\/jats:italic>. When IGFBP5 was silenced, monocytes released more IL-1\u03b2 and IL-6. NF-\u03baB downstream proteins were overexpressed. IGFBP5 interacted with ANXA2 directly. In ANXA2-silenced cells, it showed no anti-inflammatory effect. Monocytes of adjuvant-induced arthritis rats and RA patients expressed less IGFBP5 than normal controls, but its blood levels increased significantly. Adipocytes secreted large amounts of IGFBP5. This secretion was reinforced by the above sera. IGFBP5 decreased in ALI mice\u2019s blood, while its supplement exacerbated inflammation. By binding to IGF1, IGFBP5 prevented its interaction with IGF1R. An IGF1R inhibitor picropodophyllin antagonized functions of IGF1\/IGF1R too, but didn\u2019t reinforce the effects of IGFBP5.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>IGFBP5 eases inflammation by interacting with ANXA2, an activator of NF-\u03baB; as an antagonist of IGF1\/IGF1R, IGFBP5 may disrupt immune homeostasis <jats:italic>in vivo<\/jats:italic>, due to impairment of the latter\u2019s anti-inflammatory functions; excessive IGFBP from adipocytes would be a pathogenic factor in certain diseases.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2024.1539317","type":"journal-article","created":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T05:11:54Z","timestamp":1736485914000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Interaction with IGF1 overrides ANXA2-mediated anti-inflammatory functions of IGFBP5 in vivo"],"prefix":"10.3389","volume":"15","author":[{"given":"Yan","family":"Fan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Jin","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia-Qing","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abulizi","family":"Abulaiti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Opeyemi Joshua","family":"Olatunji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cong-Lan","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Zuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,1,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1007\/s12016-019-08740-1","article-title":"The innate part of the adaptive immune system","volume":"58","author":"Hillion","year":"2020","journal-title":"Clin Rev Allergy Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-021-00869-6","article-title":"Inflammasomes and adaptive immune responses","volume":"22","author":"Deets","year":"2021","journal-title":"Nat Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2015.06.001","article-title":"Monocyte and macrophage plasticity in tissue repair and regeneration","volume":"185","author":"Das","year":"2015","journal-title":"Am J Pathol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/nri1733","article-title":"Monocyte and macrophage heterogeneity","volume":"5","author":"Gordon","year":"2005","journal-title":"Nat Rev Immunol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1038\/s41392-021-00687-0","article-title":"Pattern recognition receptors in health and diseases","volume":"6","author":"Li","year":"2021","journal-title":"Signal Transduct Target Ther"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1394108","article-title":"Macrophage polarization in rheumatoid arthritis: signaling pathways, metabolic reprogramming, and crosstalk with synovial fibroblasts","volume":"15","author":"Zheng","year":"2024","journal-title":"Front Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/s44161-024-00473-5","article-title":"Immunometabolism in atherosclerotic disorders","volume":"3","author":"Fleetwood","year":"2024","journal-title":"Nat Cardiovasc Res"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.780839","article-title":"Modulation of macrophage immunometabolism: a new approach to fight infections","volume":"13","author":"Gauthier","year":"2022","journal-title":"Front Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.795626","article-title":"Metabolic enzyme triosephosphate isomerase 1 and nicotinamide phosphoribosyltransferase, two independent inflammatory indicators in rheumatoid arthritis: evidences from collagen-induced arthritis and clinical samples","volume":"12","author":"Lei","year":"2022","journal-title":"Front Immunol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"111035","DOI":"10.1016\/j.mce.2020.111035","article-title":"Disorders of IGFs and IGF-1R signaling pathways","volume":"518","author":"Forbes","year":"2020","journal-title":"Mol Cell Endocrinol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku1003","article-title":"STRING v10: protein-protein interaction networks, integrated over the tree of life","volume":"43","author":"Szklarczyk","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1111\/bph.v181.16","article-title":"White adipose tissue, a novel anti-rheumatic target: clues from its secretion capability and adipectomy-based therapy","volume":"181","author":"Ye","year":"2024","journal-title":"Brit J Pharmacol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"155132","DOI":"10.1016\/j.phymed.2023.155132","article-title":"SIRT1 inhibitors within Qing-Luo-Yin alleviated white adipose tissues-mediated inflammation in antigen-induced arthritis mice","volume":"122","author":"Ye","year":"2024","journal-title":"Phytomedicine"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.2147\/JIR.S431600","article-title":"NAMPT\/SIRT1 expression levels in white blood cells differentiate the different rheumatoid arthritis subsets: an inspiration from Traditional Chinese Medicine","volume":"16","author":"Cheng","year":"2023","journal-title":"J Inflammation Res"},{"key":"B15","doi-asserted-by":"publisher","first-page":"e2306237","DOI":"10.1002\/advs.202306237","article-title":"NINJ1 facilitates abdominal aortic aneurysm formation via blocking TLR4-ANXA2 interaction and enhancing macrophage infiltration","volume":"11","author":"Wu","year":"2024","journal-title":"Adv Sci"},{"key":"B16","doi-asserted-by":"publisher","first-page":"e1606","DOI":"10.1038\/cddis.2014.558","article-title":"Intracellular annexin A2 regulates NF-\u03baB signaling by binding to the p50 subunit: implications for gemcitabine resistance in pancreatic cancer","volume":"6","author":"Jung","year":"2015","journal-title":"Cell Death Dis"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1722","DOI":"10.3390\/nu15071722","article-title":"White adipose tissue dysfunction: pathophysiology and emergent measurements","volume":"15","author":"Santillana","year":"2023","journal-title":"Nutrients"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2018.00499","article-title":"Insulin-like growth factor binding proteins in autoimmune diseases","volume":"9","author":"Ding","year":"2018","journal-title":"Front Endocrinol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.1052457","article-title":"Insulin-like growth factor binding protein 5: Diverse roles in cancer","volume":"12","author":"Waters","year":"2022","journal-title":"Front Oncol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"108307","DOI":"10.1016\/j.mrrev.2020.108307","article-title":"Nuclear localization and actions of the insulin-like growth factor 1 (IGF-1) system components: Transcriptional regulation and DNA damage response","volume":"784","author":"Poreba","year":"2020","journal-title":"Mutat Res Rev Mutat Res"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0307154","article-title":"Annexin A2 is a soluble mediator of macrophage activation","volume":"82","author":"Swisher","year":"2007","journal-title":"J Leukoc Biol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.vph.2011.03.003","article-title":"The annexin A2 system and vascular homeostasis","volume":"54","author":"Flood","year":"2011","journal-title":"Vascul Pharmacol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2017.08.024","article-title":"Protein phosphorylation and its role in the regulation of Annexin A2 function","volume":"1861","author":"Grindheim","year":"2017","journal-title":"Biochim Biophys Acta Gen Subj"},{"key":"B24","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/s12967-015-0762-z","article-title":"Insulin-like growth factor-1 deficiency and metabolic syndrome","volume":"14","author":"Aguirre","year":"2016","journal-title":"J Transl Med"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00504.2014","article-title":"Loss of survival factors and activation of inflammatory cascades in brain sympathetic centers in type 1 diabetic mice","volume":"308","author":"Hu","year":"2015","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"B26","doi-asserted-by":"publisher","first-page":"7735","DOI":"10.1038\/srep07735","article-title":"Insulin-like growth factor-1 endues monocytes with immune suppressive ability to inhibit inflammation in the intestine","volume":"5","author":"Ge","year":"2015","journal-title":"Sci Rep"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2014.00208","article-title":"Application of insulin-like growth factor-1 in the treatment of inner ear disorders","volume":"5","author":"Yamamoto","year":"2014","journal-title":"Front Pharmacol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.03.046","article-title":"IGF1 shapes macrophage activation in response to immunometabolic challenge","volume":"19","author":"Spadaro","year":"2017","journal-title":"Cell Rep"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.2174\/1381612825666190319124009","article-title":"Circulating insulin-like growth factor-1 levels in patients with rheumatoid arthritis: a meta-analysis","volume":"25","author":"Zhao","year":"2019","journal-title":"Curr Pharm Des"},{"key":"B30","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1530\/REP-12-0225","article-title":"cAMP-dependent regulation of ovulatory response genes is amplified by IGF1 due to synergistic effects on Akt phosphorylation and NF-\u03baB transcription factors","volume":"144","author":"Mack","year":"2012","journal-title":"Reproduction"},{"key":"B31","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1038\/s41419-022-04803-y","article-title":"IGFBP5 promotes diabetic kidney disease progression by enhancing PFKFB3-mediated endothelial glycolysis","volume":"13","author":"Song","year":"2022","journal-title":"Cell Death Dis"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1539317\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T05:11:59Z","timestamp":1736485919000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1539317\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,10]]},"references-count":31,"alternative-id":["10.3389\/fimmu.2024.1539317"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2024.1539317","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,10]]},"article-number":"1539317"}}