The Journal of Practical Medicine >

2025 , Vol. 41 >Issue 18: 2953 - 2960

DOI: https://doi.org/10.3969/j.issn.1006-5725.2025.18.024

Reviews

Research progress on Th17 cell differentiation regulation mechanisms and therapeutic targets in ankylosing spondylitis

  • Mingyang YU ,
  • Jia LI ,
  • Xinzhe FENG ,
  • Jingjing BI ,
  • Cheng LI
Expand
  • Department of Joint Orthopedics，the First Affiliated to the Naval Military Medical University，Shanghai 200433，Shanghai，China

Received date: 2025-07-01

  Online published: 2025-09-25

Fold

Abstract

Ankylosing spondylitis （AS） is a chronic autoimmune disease characterized by inflammatory involvement of the axial skeleton and pathological bone formation. The T helper 17 cell （Th17 cell） subset of lymphocytes plays a central role in mediating the inflammatory processes associated with AS. This review summarizes recent advances in the regulation of Th17 cell differentiation in AS， with a focus on the complex mechanisms governed by cytokine microenvironments， transcription factor networks， and metabolic and epigenetic regulatory pathways. Key regulatory components discussed include the IL-23/STAT3 signaling axis， the CCL20/CCR6 chemotactic axis， and the master transcription factor RORγt. Additionally， this review critically evaluates emerging therapeutic strategies targeting metabolic reprogramming （e.g.， PKM2）， epigenetic regulators （e.g.， JMJD3， EZH2）， engineered exosome delivery systems， and modulators of metabolic enzymes. By analyzing the limitations of current treatment approaches， the review proposes future research directions emphasizing multi-target therapeutic strategies and highlights the importance of personalized medicine in achieving precise and effective treatment for AS. These developments reveal promising new avenues for modulating Th17-mediated immunity， offering transformative potential for the clinical management of AS.

Key words： ankylosing spondylitis; Th17 cells; IL-23/IL-17 axis; signaling pathways; targeted therapy; transcriptional regulation; bone remodeling

Cite this article

Mingyang YU , Jia LI , Xinzhe FENG , Jingjing BI , Cheng LI . Research progress on Th17 cell differentiation regulation mechanisms and therapeutic targets in ankylosing spondylitis[J]. The Journal of Practical Medicine, 2025 , 41(18) : 2953 -2960 . DOI: 10.3969/j.issn.1006-5725.2025.18.024

References

[1] SIEPER J， PODDUBNYY D. Inflammation， new bone formation and treatment options in axial spondyloarthritis ［J］. Ann Rheum Dis， 2014， 73（8）： 1439-1441. doi:10.1136/annrheumdis-2014-205464
[2] YUANYUANXU， QIPENG， QINGQINGMA， et al. scRNA + TCR-seq revealed the dual TCR pTh17 and Treg T cells involvement in autoimmune response in ankylosing spondylitis ［J］. Int Immunopharmacol， 2024， 135： 112279. doi:10.1016/j.intimp.2024.112279
[3] VORUGANTI A， BOWNESS P. New developments in our understanding of ankylosing spondylitis pathogenesis ［J］. Immunology， 2020， 161（2）： 94-102. doi:10.1111/imm.13242
[4] WON E J， KIM H J， LEE Y J， et al. CCL20 inhibition for treating inflammation in ankylosing spondylitis ［J］. Rheumatology （Oxford）， 2023， 62（12）： 4000-4005. doi:10.1093/rheumatology/kead268
[5] WANG J， ZHAO X， WAN Y Y. Intricacies of TGF-β signaling in Treg and Th17 cell biology ［J］. Cell Mol Immunol， 2023， 20（9）： 1002-1022. doi:10.1038/s41423-023-01036-7
[6] ZHANG W， LIU X， ZHU Y， et al. Transcriptional and posttranslational regulation of Th17/Treg balance in health and disease ［J］. Eur J Immunol， 2021， 51（9）： 2137-2150. doi:10.1002/eji.202048794
[7] GAGLIANI N， AMEZCUA VESELY M C， ISEPPON A， et al. Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation ［J］. Nature， 2015， 523（7559）： 221-225. doi:10.1038/nature14452
[8] BURKETT P R， MEYER ZU HORSTE G， KUCHROO V K. Pouring fuel on the fire： Th17 cells， the environment， and autoimmunity ［J］. J Clin Invest， 2015， 125（6）： 2211-2219. doi:10.1172/jci78085
[9] KERSCHBAUMER A， SMOLEN J S， FERREIRA R J O， et al. Efficacy and safety of pharmacological treatment of psoriatic arthritis： A systematic literature research informing the 2023 update of the EULAR recommendations for the management of psoriatic arthritis ［J］. Ann Rheum Dis， 2024， 83（6）： 760-774. doi:10.1136/ard-2024-225534
[10] PENNINGER P， BREZOVEC H， TSYMALA I， et al. HDAC1 fine-tunes Th17 polarization in vivo to restrain tissue damage in fungal infections ［J］. Cell Rep， 2024， 43（12）： 114993. doi:10.1016/j.celrep.2024.114993
[11] GEGE C. Retinoic acid-related orphan receptor gamma t （RORγt） inverse agonists/antagonists for the treatment of inflammatory diseases-where are we presently？ ［J］. Expert Opin Drug Discov， 2021， 16（12）： 1517-1535. doi:10.1080/17460441.2021.1948833
[12] HU Y， LI H， WANG X， et al. Activation of the aryl hydrocarbon receptor alleviates Sj?gren's syndrome by promoting Bregs differentiation ［J］. Int Immunopharmacol， 2025， 158： 114812. doi:10.1016/j.intimp.2025.114812
[13] CHEN W， WANG P， XIE Y， et al. Histone lactylation-augmented IRF4 is implicated in arsenite-induced liver fibrosis via modulating Th17 cell differentiation ［J］. Chem Biol Interact， 2025， 414： 111507. doi:10.1016/j.cbi.2025.111507
[14] XIE Y， CHAI M， XING Y， et al. miRNA let-7f-5p-encapsulated labial gland MSC-derived EVs ameliorate experimental Sj?gren's syndrome by suppressing Th17 cells via targeting RORC/IL-17A signaling axis ［J］. J Nanobiotechnology， 2025， 23（1）： 228. doi:10.1186/s12951-025-03308-y
[15] OHARA D， TAKEUCHI Y， HIROTA K. Type 17 immunity： novel insights into intestinal homeostasis and autoimmune pathogenesis driven by gut-primed T cells［J］. Cell Mol Immunol， 2024， 21（11）： 1183-1200. doi:10.1038/s41423-024-01218-x
[16] NIU D， YUE S Y， WANG X， et al. High glucose intake exacerbates experimental autoimmune prostatitis through mitochondrial reactive oxygen species-dependent TGF-β activation-mediated Th17 differentiation ［J］. Int Immunopharmacol， 2024， 130： 111682. doi:10.1016/j.intimp.2024.111682
[17] WILCK N， MATUS M G， KEARNEY S M， et al. Salt-responsive gut commensal modulates TH17 axis and disease ［J］. Nature， 2017， 551（7682）： 585-589. doi:10.1038/nature24628
[18] DAMASCENO L E A， PRADO D S， VERAS F P， et al. PKM2 promotes Th17 cell differentiation and autoimmune inflammation by fine-tuning STAT3 activation ［J］. J Exp Med， 2020， 217（10）： e20190613. doi:10.1084/jem.20190613
[19] LI Y， HE M， XU J， et al. Hypoxia Exposure Promotes Th17 Cell Differentiation Through Activin A-PKM2 Axis to Exacerbate Autoimmune and Autoinflammatory Diseases ［J］. FASEB J， 2025， 39（12）： e70696. doi:10.1096/fj.202500719r
[20] YANG K L， LEJEUNE A， CHANG G， et al. Microbial-derived antigens and metabolites in spondyloarthritis ［J］. Semin Immunopathol， 2021， 43（2）： 163-172. doi:10.1007/s00281-021-00844-1
[21] TAN T G， SEFIK E， GEVA-ZATORSKY N， et al. Identifying species of symbiont bacteria from the human gut that， alone， can induce intestinal Th17 cells in mice ［J］. Proc Natl Acad Sci U S A， 2016， 113（50）： E8141-E8150. doi:10.1073/pnas.1617460113
[22] CHEN Y， LIU W， XU X， et al. The Role of H3K27me3-Mediated Th17 Differentiation in Ankylosing Spondylitis ［J］. Inflammation， 2024， 47（5）： 1685-1698. doi:10.1007/s10753-024-02002-9
[23] SU Q Y， ZHENG J W， YANG J Y， et al. Levels of Peripheral Th17 Cells and Th17-Related Cytokines in Patients with Ankylosing Spondylitis： A Meta-analysis ［J］. Adv Ther， 2022， 39（10）： 4423-4439. doi:10.1007/s12325-022-02240-z
[24] NAVID F， HOLT V， COLBERT R A. The enigmatic role of HLA-B*27 in spondyloarthritis pathogenesis ［J］. Semin Immunopathol， 2021， 43（2）： 235-243. doi:10.1007/s00281-021-00838-z
[25] WEI Y， ZHANG S， SHAO F， et al. Ankylosing spondylitis： From pathogenesis to therapy ［J］. Int Immunopharmacol， 2025， 145： 113709. doi:10.1016/j.intimp.2024.113709
[26] WANG S， SONG R， WANG Z， et al. S100A8/A9 in Inflammation ［J］. Front Immunol， 2018， 9： 1298. doi:10.3389/fimmu.2018.01298
[27] FELD J， CHANDRAN V， HAROON N， et al. Axial disease in psoriatic arthritis and ankylosing spondylitis： A critical comparison ［J］. Nat Rev Rheumatol， 2018， 14（6）： 363-371. doi:10.1038/s41584-018-0006-8
[28] LEI L， WEN Z， CAO M， et al. The emerging role of Piezo1 in the musculoskeletal system and disease ［J］. Theranostics， 2024， 14（10）： 3963-3983. doi:10.7150/thno.96959
[29] YI K， JO S， SONG W， et al. Analysis of Single-Cell Transcriptome and Surface Protein Expression in Ankylosing Spondylitis Identifies OX40-Positive and Glucocorticoid-Induced Tumor Necrosis Factor Receptor-Positive Pathogenic Th17 Cells ［J］. Arthritis Rheumatol， 2023， 75（7）： 1176-1186. doi:10.1002/art.42476
[30] ALTIN?NDER ?， KAYA M， YENTüR S P， et al. Thymic gene expression analysis reveals a potential link between HIF-1A and Th17/Treg imbalance in thymoma associated myasthenia gravis ［J］. J Neuroinflammation， 2024， 21（1）： 126. doi:10.1186/s12974-024-03095-7
[31] TANG Z， JIN L， YANG Y. The dual role of IL-17 in periodontitis regulating immunity and bone homeostasis ［J］. Front Immunol， 2025， 16： 1578635. doi:10.3389/fimmu.2025.1578635
[32] YANG X， YANG J， XING X， et al. Increased frequency of Th17 cells in systemic sclerosis is related to disease activity and collagen overproduction ［J］. Arthritis Res Ther， 2014， 16（1）： R4. doi:10.1186/ar4430
[33] 姬原原， 包景泊， 赵旭， 等. 白介素17F促进大鼠成骨细胞增殖、矿化和Runx2、Osterix的表达 ［J］. 山东大学学报（医学版）， 2017， 55（8）： 24-29.
[34] CHEUNG K L， ZHAO L， SHARMA R， et al. Class IIa HDAC4 and HDAC7 cooperatively regulate gene transcription in Th17 cell differentiation ［J］. Proc Natl Acad Sci U S A， 2024， 121（18）： e2312111121. doi:10.1073/pnas.2312111121
[35] ZHU X， WANG P， ZHAN X， et al. USP1-regulated reciprocal differentiation of Th17 cells and Treg cells by deubiquitinating and stabilizing TAZ ［J］. Cell Mol Immunol， 2023， 20（3）： 252-263. doi:10.1038/s41423-022-00969-9
[36] 张玉红， 单新洁， 周俊. miR-155通过SOCS1/STAT3途径调控类风湿性关节炎中炎症反应和Th17/Treg失衡 ［J］. 实用医学杂志， 2024， 40（13）： 1791-1796.
[37] XU F， GUANGHAO C， LIANG Y， et al. Treg-promoted New Bone Formation Through Suppressing TH17 by Secreting Interleukin-10 in Ankylosing Spondylitis ［J］. Spine （Phila Pa 1976）， 2019， 44（23）： E1349-E1355. doi:10.1097/brs.0000000000003169
[38] KARMACHARYA P， DUARTE-GARCIA A， DUBREUIL M， et al. Effect of Therapy on Radiographic Progression in Axial Spondyloarthritis： A Systematic Review and Meta-Analysis ［J］. Arthritis Rheumatol， 2020， 72（5）： 733-749. doi:10.1002/art.41206
[39] KIM J W， YOON J S， PARK S， et al. Risk of cardiovascular disease with high-dose versus low-dose use of non-steroidal anti-inflammatory drugs in ankylosing spondylitis ［J］. Ann Rheum Dis， 2024， 83（8）： 1028-1033. doi:10.1136/ard-2023-225406
[40] KOPP T I， DELCOIGNE B， ARKEMA E V， et al. Risk of neuroinflammatory events in arthritis patients treated with tumour necrosis factor alpha inhibitors： A collaborative population-based cohort study from Denmark and Sweden ［J］. Ann Rheum Dis， 2020， 79（5）： 566-572. doi:10.1136/annrheumdis-2019-216693
[41] FAUNY M， MOULIN D， D'AMICO F， et al. Paradoxical gastrointestinal effects of interleukin-17 blockers ［J］. Ann Rheum Dis， 2020， 79（9）： 1132-1138. doi:10.1136/annrheumdis-2020-217927
[42] BENAVENT D， NAVARRO-COMPáN V. Exploring the latest advances in axial spondyloarthritis management ［J］. Nat Rev Rheumatol， 2024， 20（2）： 79-80. doi:10.1038/s41584-023-01072-7
[43] 姜克悦， 刘磊， 王文惠. 枸橼酸托法替布治疗活动性强直性脊柱炎的随机对照研究 ［J］. 实用医学杂志， 2022， 38（11）： 1415-1418.
[44] WORTH C， AL-MOSSAWI M H， MACDONALD J， et al. Granulocyte-macrophage colony-stimulating factor neutralisation in patients with axial spondyloarthritis in the UK （NAMASTE）： A randomised， double-blind， placebo-controlled， phase 2 trial ［J］. Lancet Rheumatol， 2024， 6（8）： e537-e545. doi:10.1016/s2665-9913(24)00099-7
[45] JAAFAR H M， AMEEN D M H， MOHAMMAD T A M， et al. The effects of nanocurcumin on immune-related factors in the ankylosing spondylitis patients： A double-blind， randomized， placebo-controlled clinical trial ［J］. Mol Biol Rep， 2025， 52（1）： 324. doi:10.1007/s11033-025-10397-3
[46] GRACEY E， HROMADOVá D， LIM M， et al. TYK2 inhibition reduces type 3 immunity and modifies disease progression in murine spondyloarthritis ［J］. J Clin Invest， 2020， 130（4）： 1863-1878. doi:10.1172/jci126567
[47] CRIBBS A P， TERLECKI-ZANIEWICZ S， PHILPOTT M， et al. Histone H3K27me3 demethylases regulate human Th17 cell development and effector functions by impacting on metabolism ［J］. Proc Natl Acad Sci U S A， 2020， 117（11）： 6056-6066. doi:10.1073/pnas.1919893117
[48] CHEN L， BAI J， PENG D， et al. SZB120 Exhibits Immunomodulatory Effects by Targeting eIF2α to Suppress Th17 Cell Differentiation ［J］. J Immunol， 2021， 206（5）： 953-962. doi:10.4049/jimmunol.2000036
[49] ROSENZWEIG H L， VANCE E E， ASARE-KONADU K， et al. Card9/neutrophil signalling axis promotes IL-17A-mediated ankylosing spondylitis ［J］. Ann Rheum Dis， 2024， 83（2）： 214-222. doi:10.1136/ard-2022-223146
[50] OGDIE A， REDDY S M， GILLESPIE S H， et al. Guselkumab versus golimumab in patients with active psoriatic arthritis and inadequate response to an initial tumor necrosis factor inhibitor： Study protocol for EVOLUTION， a pragmatic， phase 3b， open-label， randomized， controlled effectiveness trial ［J］. Trials， 2025， 26（1）： 96. doi:10.1186/s13063-025-08777-y
Options
Outlines

/

〈 〉