{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T05:32:56Z","timestamp":1777699976381,"version":"3.51.4"},"reference-count":35,"publisher":"IMR Press","issue":"4","license":[{"start":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T00:00:00Z","timestamp":1777248000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Guangxi Natural Science Foundation Project","award":["2025GXNSFAA069182"],"award-info":[{"award-number":["2025GXNSFAA069182"]}]},{"DOI":"10.13039\/501100004735","name":"Natural Science Foundation of Hunan Province","doi-asserted-by":"crossref","award":["2023JJ70050"],"award-info":[{"award-number":["2023JJ70050"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Guangxi Zhuang Autonomous Region Health Commission Self-funded Scientific Research Project","award":["Z-A20251080"],"award-info":[{"award-number":["Z-A20251080"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background: While the systemic metabolic role of fibroblast growth factor 21 (FGF21) is well-established, its function in retinal homeostasis and its link to retinal diseases like age-related macular degeneration (AMD) and diabetic retinopathy (DR) remains poorly understood. This study investigated the impact of endogenous FGF21 deficiency on the retinal immune microenvironment. Methods: Retinal structure was assessed in FGF21 KO and wild-type mice using spectral-domain optical coherence tomography. Transcriptomic profiles of the retina\/choroid were analyzed by RNA-seq. Differentially expressed genes (DEGs) were identified (DESeq2, FDR &lt;0.05), clustered, and interrogated by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Immune-cell composition was inferred with ImmuCellAI. Results: FGF21 KO mice showed no overt retinal structural defects under baseline conditions. Nevertheless, 449 DEGs were identified (293 up, 156 down in knockout). Pathway analysis revealed significant enrichment of cytokine\u2013cytokine receptor interaction, chemokine signaling, and Jak-STAT cascades. Immune deconvolution indicated a significant increase in M2-polarised macrophages (p &lt; 0.01) without change in total macrophage number. Expression of key inflammatory mediators including Il1b was concordantly altered. Conclusions: This work establishes endogenous FGF21 as a crucial local immunomodulator and defines a novel mechanistic link to retinal disease susceptibility, supporting its further exploration as a therapeutic target.<\/jats:p>","DOI":"10.31083\/fbl47702","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T09:29:27Z","timestamp":1777454967000},"source":"Crossref","is-referenced-by-count":0,"title":["Effect of Endogenous FGF21 Deficiency on the Inflammatory Microenvironment of the Retina"],"prefix":"10.31083","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2762-3561","authenticated-orcid":true,"given":"Ting-ting","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Aier Eye Hospital, Jinan University, 510071 Guangzhou, Guangdong, China"},{"name":"Department of Fundus Diseases, Nanning Aier Eye Hospital, 530000 Nanning, Guangxi, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9763-7199","authenticated-orcid":true,"given":"Ming-kai","family":"Chang","sequence":"additional","affiliation":[{"name":"School of Life Science, Northeast Agricultural University, 150030 Harbin, Heilongjiang, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bai-yun","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Fundus Diseases, Nanning Aier Eye Hospital, 530000 Nanning, Guangxi, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0546-562X","authenticated-orcid":true,"given":"Hao-ran","family":"Guo","sequence":"additional","affiliation":[{"name":"School of Life Science, Northeast Agricultural University, 150030 Harbin, Heilongjiang, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2082-1407","authenticated-orcid":true,"given":"Yu-tong","family":"Han","sequence":"additional","affiliation":[{"name":"School of Life Science, Northeast Agricultural University, 150030 Harbin, Heilongjiang, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3360-8082","authenticated-orcid":true,"given":"Wen-fei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Fundus Diseases, Nanning Aier Eye Hospital, 530000 Nanning, Guangxi, China"},{"name":"School of Life Science, Northeast Agricultural University, 150030 Harbin, Heilongjiang, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"16242","published-online":{"date-parts":[[2026,4,27]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Wong WL, Su X, Li X, Cheung CMG, Klein R, Cheng CY, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. The Lancet. Global Health. 2014; 2: e106\u2013e116.","DOI":"10.1016\/S2214-109X(13)70145-1"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Prida E, \u00c1lvarez-Delgado S, P\u00e9rez-Lois R, Soto-Tielas M, Estany-Gestal A, Fern\u00f8 J, et al. Liver Brain Interactions: Focus on FGF21 a Systematic Review. International Journal of Molecular Sciences. 2022; 23: 13318.","DOI":"10.3390\/ijms232113318"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Nauck MA, Wefers J, Meier JJ. Treatment of type 2 diabetes: challenges, hopes, and anticipated successes. The Lancet. Diabetes & Endocrinology. 2021; 9: 525\u2013544.","DOI":"10.1016\/S2213-8587(21)00113-3"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Kang K, Xu P, Wang M, Chunyu J, Sun X, Ren G, et al. FGF21 attenuates neurodegeneration through modulating neuroinflammation and oxidant-stress. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie. 2020; 129: 110439.","DOI":"10.1016\/j.biopha.2020.110439"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Li JY, Wang N, Khoso MH, Shen CB, Guo MZ, Pang XX, et al. FGF-21 Elevated IL-10 Production to Correct LPS-Induced Inflammation. Inflammation. 2018; 41: 751\u2013759.","DOI":"10.1007\/s10753-018-0729-3"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Youm YH, Horvath TL, Mangelsdorf DJ, Kliewer SA, Dixit VD. Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution. Proceedings of the National Academy of Sciences of the United States of America. 2016; 113: 1026\u20131031.","DOI":"10.1073\/pnas.1514511113"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Fu Z, Gong Y, Liegl R, Wang Z, Liu CH, Meng SS, et al. FGF21 Administration Suppresses Retinal and Choroidal Neovascularization in Mice. Cell Reports. 2017; 18: 1606\u20131613.","DOI":"10.1016\/j.celrep.2017.01.014"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Fu Z, Lundgren P, Pivodic A, Yagi H, Harman JC, Yang J, et al. FGF21 via mitochondrial lipid oxidation promotes physiological vascularization in a mouse model of Phase I ROP. Angiogenesis. 2023; 26: 409\u2013421.","DOI":"10.1007\/s10456-023-09872-x"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"Fu Z, Wang Z, Liu CH, Gong Y, Cakir B, Liegl R, et al. Fibroblast Growth Factor 21 Protects Photoreceptor Function in Type 1 Diabetic Mice. Diabetes. 2018; 67: 974\u2013985.","DOI":"10.2337\/db17-0830"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Tomita Y, Fu Z, Wang Z, Cakir B, Cho SS, Britton W, et al. Long-Acting FGF21 Inhibits Retinal Vascular Leakage in In Vivo and In Vitro Models. International Journal of Molecular Sciences. 2020; 21: 1188.","DOI":"10.3390\/ijms21041188"},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"Zhao T, Wang W, Gao K, Li S, Jiang Y, Yang Z, et al. Fibroblast growth factor-21 alleviates phenotypic characteristics of dry age-related macular degeneration in mice. Experimental Eye Research. 2022; 218: 109014.","DOI":"10.1016\/j.exer.2022.109014"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Research. 2019; 47: D607\u2013D613.","DOI":"10.1093\/nar\/gky1131"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"Chin CH, Chen SH, Wu HH, Ho CW, Ko MT, Lin CY. cytoHubba: identifying hub objects and sub-networks from complex interactome. BMC Systems Biology. 2014; 8 Suppl 4: S11.","DOI":"10.1186\/1752-0509-8-S4-S11"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Wu T, Hu E, Xu S, Chen M, Guo P, Dai Z, et al. clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation (Cambridge (Mass.)). 2021; 2: 100141.","DOI":"10.1016\/j.xinn.2021.100141"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"Miao YR, Zhang Q, Lei Q, Luo M, Xie GY, Wang H, et al. ImmuCellAI: A Unique Method for Comprehensive T-Cell Subsets Abundance Prediction and its Application in Cancer Immunotherapy. Advanced Science (Weinheim, Baden-Wurttemberg, Germany). 2020; 7: 1902880.","DOI":"10.1002\/advs.201902880"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"Miao YR, Xia M, Luo M, Luo T, Yang M, Guo AY. ImmuCellAI-mouse: a tool for comprehensive prediction of mouse immune cell abundance and immune microenvironment depiction. Bioinformatics (Oxford, England). 2022; 38: 785\u2013791.","DOI":"10.1093\/bioinformatics\/btab711"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"Geng L, Lam KSL, Xu A. The therapeutic potential of FGF21 in metabolic diseases: from bench to clinic. Nature Reviews. Endocrinology. 2020; 16: 654\u2013667.","DOI":"10.1038\/s41574-020-0386-0"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"Tan H, Yue T, Chen Z, Wu W, Xu S, Weng J. Targeting FGF21 in cardiovascular and metabolic diseases: from mechanism to medicine. International Journal of Biological Sciences. 2023; 19: 66\u201388.","DOI":"10.7150\/ijbs.73936"},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"Coskun T, Bina HA, Schneider MA, Dunbar JD, Hu CC, Chen Y, et al. Fibroblast growth factor 21 corrects obesity in mice. Endocrinology. 2008; 149: 6018\u20136027.","DOI":"10.1210\/en.2008-0816"},{"key":"ref20","doi-asserted-by":"publisher","unstructured":"Xu J, Lloyd DJ, Hale C, Stanislaus S, Chen M, Sivits G, et al. Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes. 2009; 58: 250\u2013259.","DOI":"10.2337\/db08-0392"},{"key":"ref21","doi-asserted-by":"publisher","unstructured":"Geng L, Liao B, Jin L, Huang Z, Triggle CR, Ding H, et al. Exercise Alleviates Obesity-Induced Metabolic Dysfunction via Enhancing FGF21 Sensitivity in Adipose Tissues. Cell Reports. 2019; 26: 2738\u20132752.e4.","DOI":"10.1016\/j.celrep.2019.02.014"},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"Hotta Y, Nakamura H, Konishi M, Murata Y, Takagi H, Matsumura S, et al. Fibroblast growth factor 21 regulates lipolysis in white adipose tissue but is not required for ketogenesis and triglyceride clearance in liver. Endocrinology. 2009; 150: 4625\u20134633.","DOI":"10.1210\/en.2009-0119"},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"Liang Q, Zhong L, Zhang J, Wang Y, Bornstein SR, Triggle CR, et al. FGF21 maintains glucose homeostasis by mediating the cross talk between liver and brain during prolonged fasting. Diabetes. 2014; 63: 4064\u20134075.","DOI":"10.2337\/db14-0541"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"Biasella F, Pl\u00f6ssl K, Baird PN, Weber BHF. The extracellular microenvironment in immune dysregulation and inflammation in retinal disorders. Frontiers in Immunology. 2023; 14: 1147037.","DOI":"10.3389\/fimmu.2023.1147037"},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"Murakami Y, Ishikawa K, Nakao S, Sonoda KH. Innate immune response in retinal homeostasis and inflammatory disorders. Progress in Retinal and Eye Research. 2020; 74: 100778.","DOI":"10.1016\/j.preteyeres.2019.100778"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"Perez VL, Caspi RR. Immune mechanisms in inflammatory and degenerative eye disease. Trends in Immunology. 2015; 36: 354\u2013363.","DOI":"10.1016\/j.it.2015.04.003"},{"key":"ref27","doi-asserted-by":"publisher","unstructured":"Chen Y, Zhang X, Yang L, Li M, Li B, Wang W, et al. Decreased PPAR-\u03b3 expression in the conjunctiva and increased expression of TNF-\u03b1 and IL-1\u03b2 in the conjunctiva and tear fluid of dry eye mice. Molecular Medicine Reports. 2014; 9: 2015\u20132023.","DOI":"10.3892\/mmr.2014.2041"},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"Mukohda M, Stump M, Ketsawatsomkron P, Hu C, Quelle FW, Sigmund CD. Endothelial PPAR-\u03b3 provides vascular protection from IL-1\u03b2-induced oxidative stress. American Journal of Physiology. Heart and Circulatory Physiology. 2016; 310: H39\u2013H48.","DOI":"10.1152\/ajpheart.00490.2015"},{"key":"ref29","doi-asserted-by":"publisher","unstructured":"Abdalla HB, Napimoga MH, Lopes AH, de Macedo Maganin AG, Cunha TM, Van Dyke TE, et al. Activation of PPAR-\u03b3 induces macrophage polarization and reduces neutrophil migration mediated by heme oxygenase 1. International Immunopharmacology. 2020; 84: 106565.","DOI":"10.1016\/j.intimp.2020.106565"},{"key":"ref30","doi-asserted-by":"publisher","unstructured":"Jarosova R, Ondrackova P, Leva L, Nedbalcova K, Vicenova M, Masek J, et al. Cytokine expression by CD163+ monocytes in healthy and Actinobacillus pleuropneumoniae-infected pigs. Research in Veterinary Science. 2022; 152: 1\u20139.","DOI":"10.1016\/j.rvsc.2022.07.015"},{"key":"ref31","doi-asserted-by":"publisher","unstructured":"Padovani-Claudio DA, Morales MS, Smith TE, Ontko CD, Namburu NS, Palmer SA, et al. Induction, amplification, and propagation of diabetic retinopathy-associated inflammatory cytokines between human retinal microvascular endothelial and M\u00fcller cells and in the mouse retina. Cellular Signalling. 2024; 124: 111454.","DOI":"10.1016\/j.cellsig.2024.111454"},{"key":"ref32","doi-asserted-by":"publisher","unstructured":"Garcia MJ, Beall AL, Morales MS, Beatty NJ, Palmer SA, Jhala M, et al. IL-8 receptor signaling as a novel target for angiogenic retinopathies. Angiogenesis. 2025; 29: 2.","DOI":"10.1007\/s10456-025-10015-7"},{"key":"ref33","doi-asserted-by":"publisher","unstructured":"Gao S, Li C, Zhu Y, Wang Y, Sui A, Zhong Y, et al. PEDF mediates pathological neovascularization by regulating macrophage recruitment and polarization in the mouse model of oxygen-induced retinopathy. Scientific Reports. 2017; 7: 42846.","DOI":"10.1038\/srep42846"},{"key":"ref34","doi-asserted-by":"publisher","unstructured":"Yang Y, Liu F, Tang M, Yuan M, Hu A, Zhan Z, et al. Macrophage polarization in experimental and clinical choroidal neovascularization. Scientific Reports. 2016; 6: 30933.","DOI":"10.1038\/srep30933"},{"key":"ref35","doi-asserted-by":"publisher","unstructured":"Zhu Y, Zhang L, Lu Q, Gao Y, Cai Y, Sui A, et al. Identification of different macrophage subpopulations with distinct activities in a mouse model of oxygen-induced retinopathy. International Journal of Molecular Medicine. 2017; 40: 281\u2013292.","DOI":"10.3892\/ijmm.2017.3022"}],"container-title":["Frontiers in Bioscience-Landmark"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/31\/4\/10.31083\/FBL47702","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T09:29:29Z","timestamp":1777454969000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/31\/4\/10.31083\/FBL47702"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,27]]},"references-count":35,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026]]}},"alternative-id":["S2768-6701(26)02069-1"],"URL":"https:\/\/doi.org\/10.31083\/fbl47702","relation":{},"ISSN":["2768-6701","2768-6698"],"issn-type":[{"value":"2768-6701","type":"print"},{"value":"2768-6698","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,27]]},"article-number":"47702"}}