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The role of IL-17 and Th17 cells in keloid pathogenesis

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Abstract

Keloids are characterized histologically by excessive fibroblast proliferation and connective tissue deposition, and clinically by scar tissue extending beyond the original site of skin injury. These scars can cause pruritus, pain, physical disfigurement, anxiety, and depression. As a result, keloid patients often have a diminished quality of life with a disproportionate burden on ethnic minorities. Despite advances in understanding keloid pathology, there is no effective Food and Drug Administration (FDA)-approved pharmacotherapy. Recent studies have highlighted the possible pathologic role of T helper (Th)17 cells and interleukin (IL)-17 in keloid formation, as well as their implication in other inflammatory disorders. This systematic review characterizes the role of Th17 cells and IL-17 in keloid pathogenesis, highlighting this pathway as a potential therapeutic target. Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a comprehensive search on PubMed, Embase, MEDLINE, and Web of Science databases on June 5, 2024. The search included terms related to Th17 cells, IL-17, and keloids. Thirteen studies met the inclusion criteria, comprising basic science and bioinformatic studies focusing on Th17 cells and IL-17. Key findings include increased Th17 cell infiltration and IL-17 expression in keloids, IL-17’s role in amplifying the inflammatory and fibrotic response via the promotion of IL-6 expression, and IL-17’s involvement in upregulating fibrotic markers via SDF-1 and HIF-1α pathways. IL-17 also activates the transforming growth factor beta (TGF-β)/Smad pathway in keloid fibroblasts. Th17 cells and IL-17 significantly contribute to the inflammatory and fibrotic processes in keloid pathogenesis. Therefore, targeting the IL-17 pathway offers a potential new therapeutic target to improve keloid patients’ outcomes. Future research could further elucidate the role of Th17 cells and IL-17 in keloid pathogenesis and assess the safety and efficacy of targeting this pathway in human studies.

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References

  1. Mony MP et al (2023) Updated Rev Hypertrophic Scarring Cells, 12(5)

  2. Limandjaja GC et al (2021) Hypertrophic scars and keloids: overview of the evidence and practical guide for differentiating between these abnormal scars. Exp Dermatol 30(1):146–161

    Article  PubMed  CAS  Google Scholar 

  3. Betarbet U, Blalock TW (2020) Keloids: a review of etiology, Prevention, and treatment. J Clin Aesthet Dermatol 13(2):33–43

    PubMed  PubMed Central  Google Scholar 

  4. Bijlard E et al (2017) Burden of Keloid Disease: a cross-sectional health-related quality of Life Assessment. Acta Derm Venereol 97(2):225–229

    Article  PubMed  Google Scholar 

  5. Lu W, Chu H, Zheng X (2021) Effects on quality of life and psychosocial wellbeing in Chinese patients with keloids. Am J Transl Res 13(3):1636–1642

    PubMed  PubMed Central  Google Scholar 

  6. Olopoenia A et al (2024) Demographics, clinical characteristics, and treatment patterns among keloid patients: United States Electronic Health Records (EHR) Database Study. Int J Dermatol

  7. Sarah McGinty WJS, Keloid (2023) [Internet] [cited September 20, 2023; https://www.ncbi.nlm.nih.gov/books/NBK507899/

  8. Insights FM (2023) Keloid Treatment Market Outlook (2023 to 2033). [cited June 26, 2024

  9. Wang ZC et al (2020) The roles of inflammation in Keloid and hypertrophic scars. Front Immunol 11:603187

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Lee CC et al (2023) An updated review of the immunological mechanisms of keloid scars. Front Immunol 14:1117630

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Hong YK et al (2023) Inflammation in Wound Healing and pathological scarring. Adv Wound Care (New Rochelle) 12(5):288–300

    Article  PubMed  Google Scholar 

  12. Ghazizadeh M (2007) Essential role of IL-6 signaling pathway in keloid pathogenesis. J Nippon Med Sch 74(1):11–22

    Article  PubMed  CAS  Google Scholar 

  13. Do DV et al (2012) Interleukin-18 system plays an important role in keloid pathogenesis via epithelial–mesenchymal interactions. Br J Dermatol 166(6):1275–1288

    Article  PubMed  CAS  Google Scholar 

  14. Zhang D, Li B, Zhao M (2021) Therapeutic strategies by regulating Interleukin Family to suppress inflammation in hypertrophic scar and keloid. Front Pharmacol 12:667763

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Lee AR et al (2023) Establishment of a humanized mouse model of keloid diseases following the migration of patient immune cells to the lesion: patient-derived keloid xenograft (PDKX) model. Exp Mol Med 55(8):1713–1719

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Zhang XY, Wu XF, Li DQ (2023) The communication from Immune cells to the fibroblasts in Keloids: implications for Immunotherapy. Int J Mol Sci, 24(20)

  17. Tang Y et al (2023) Tissue RNA sequencing reveals novel biomarkers Associated with Postoperative Keloid recurrence. J Clin Med, 12(17)

  18. Yan Q, Li B (2022) TRAF3IP2 regulated by FOXO4 affects fibroblast proliferation, migration, and extracellular matrix deposition in keloid through the TGF-β1/Smad pathway. J Cosmet Dermatol 21(10):5148–5155

    Article  PubMed  Google Scholar 

  19. Liu Y et al (2012) IL-17 contributes to cardiac fibrosis following experimental autoimmune myocarditis by a PKCβ/Erk1/2/NF-κB-dependent signaling pathway. Int Immunol 24(10):605–612

    Article  PubMed  CAS  Google Scholar 

  20. Jiang D et al (2023) Interleukin-17A plays a key role in pulmonary fibrosis following Propionibacterium acnes-induced sarcoidosis-like inflammation. Exp Biol Med (Maywood) 248(14):1181–1190

    Article  PubMed  CAS  Google Scholar 

  21. Nie YJ et al (2022) Role of IL-17 family cytokines in the progression of IPF from inflammation to fibrosis. Mil Med Res 9(1):21

    PubMed  PubMed Central  CAS  Google Scholar 

  22. Meng F et al (2012) Interleukin-17 signaling in inflammatory, kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology 143(3):765–776e3

    Article  PubMed  CAS  Google Scholar 

  23. Sisto M, Lisi S (2023) Targeting Interleukin-17 as a Novel Treatment option for Fibrotic diseases. J Clin Med, 13(1)

  24. Weng CH et al (2020) Interleukin-17A induces renal fibrosis through the ERK and Smad signaling pathways. Biomed Pharmacother 123:109741

    Article  PubMed  CAS  Google Scholar 

  25. Ekstein SF et al (2021) Keloids: a review of therapeutic management. Int J Dermatol 60(6):661–671

    Article  PubMed  CAS  Google Scholar 

  26. El Kinani M, Duteille F et al (2020) Scar Epidemiology and Consequences, in Textbook on Scar Management: State of the Art Management and Emerging Technologies, L. Téot, Editors. Springer Copyright 2020, The Author(s). Cham (CH). pp. 45 – 9

  27. Al Zahrani RA et al (2023) Comprehensive Analysis of Current Treatment approaches for keloids in Pediatrics: a systematic review. Cureus 15(12):e50290

    PubMed  PubMed Central  Google Scholar 

  28. Gauglitz GG (2013) Management of keloids and hypertrophic scars: current and emerging options. Clin Cosmet Investig Dermatol 6:103–114

    Article  PubMed  PubMed Central  Google Scholar 

  29. Li Y et al (2021) The polygenic map of keloid fibroblasts reveals Fibrosis-Associated gene alterations in inflammation and Immune responses. Front Immunol 12:810290

    Article  PubMed  CAS  Google Scholar 

  30. Zhou B et al (2024) Identification and validation of CCR5 linking keloid with atopic dermatitis through comprehensive bioinformatics analysis and machine learning. Front Immunol 15:1309992

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Zheng W, Lin G, Wang Z (2021) Bioinformatics study on different gene expression profiles of fibroblasts and vascular endothelial cells in keloids. Med (Baltim) 100(47):e27777

    Article  CAS  Google Scholar 

  32. Wu J et al (2020) RNA sequencing keloid Transcriptome associates Keloids with Th2, Th1, Th17/Th22, and JAK3-Skewing. Front Immunol 11:597741

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Zhou B et al (2024) Identification and validation of CCR5 linking keloid with atopic dermatitis through comprehensive bioinformatics analysis and machine learning. Front Immunol 15:14

    Google Scholar 

  34. Zhang Q et al (2009) Tumor-like stem cells derived from human keloid are governed by the inflammatory niche driven by IL-17/IL-6 axis. PLoS ONE 4(11):e7798

    Article  PubMed  PubMed Central  Google Scholar 

  35. Fujita M et al (2019) NEDD4 is involved in inflammation development during keloid formation. J Invest Dermatol 139(2):333–341

    Article  PubMed  CAS  Google Scholar 

  36. Shi G, Jin Y (2010) Role of Oct4 in maintaining and regaining stem cell pluripotency. Stem Cell Res Ther 1(5):39

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Granick M et al (2011) Telomere dynamics in keloids. Eplasty 11:e15

    PubMed  PubMed Central  Google Scholar 

  38. Kim KW et al (2007) Up-regulation of stromal cell-derived factor 1 (CXCL12) production in rheumatoid synovial fibroblasts through interactions with T lymphocytes: role of interleukin-17 and CD40L-CD40 interaction. Arthritis Rheum 56(4):1076–1086

    Article  PubMed  CAS  Google Scholar 

  39. Lee SY et al (2020) IL-17 Induced Stromal Cell-Derived Factor-1 and profibrotic factor in keloid-derived skin fibroblasts < i > via the STAT3 pathway. Inflammation 43(2):664–672

    Article  PubMed  CAS  Google Scholar 

  40. Kohli L, Roth KA (2010) Autophagy Am J Pathol 176(3):1065–1071

    Article  PubMed  CAS  Google Scholar 

  41. Lee SY et al (2022) IL-17 induces Autophagy Dysfunction to promote inflammatory cell death and fibrosis in keloid fibroblasts < i > via the STAT3 and HIF-1a Dependent Signaling pathways. Front Immunol 13:9

    Google Scholar 

  42. Li S et al (2022) Relative perfusion index: an objective, quantitative and noninvasive method for evaluating the severity of keloids. Lasers Surg Med 54(8):1071–1081

    Article  PubMed  Google Scholar 

  43. Lee SY et al (2022) IL-17 induces Autophagy Dysfunction to promote inflammatory cell death and fibrosis in keloid fibroblasts via the STAT3 and HIF-1α Dependent Signaling pathways. Front Immunol 13:888719

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Nemer G et al (2020) A novel TRAF3IP2 variant causing familial scarring alopecia with mixed features of discoid lupus erythematosus and folliculitis decalvans. Clin Genet 98(2):116–125

    Article  PubMed  CAS  Google Scholar 

  45. Das NA et al (2018) TRAF3IP2 mediates TWEAK/TWEAKR-induced pro-fibrotic responses in cultured cardiac fibroblasts and the heart. J Mol Cell Cardiol 121:107–123

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Hinks TSC et al (2019) Activation and in vivo evolution of the MAIT Cell Transcriptome in mice and humans reveals tissue repair functionality. Cell Rep 28(12):3249–3262e5

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Nurzat Y et al (2023) Invariant chain of the MAIT-TCR vα7.2-Jα33 as a novel diagnostic biomarker for keloids. Exp Dermatol 32(2):186–197

    Article  PubMed  CAS  Google Scholar 

  48. Lee SY et al (2020) IL-17 Induced Stromal cell–derived Factor-1 and profibrotic factor in keloid-derived skin fibroblasts via the STAT3 pathway. Inflammation 43(2):664–672

    Article  PubMed  CAS  Google Scholar 

  49. Suzuki E et al (2014) The IL-23/IL-17 axis in psoriatic arthritis. Autoimmun Rev 13(4–5):496–502

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Sakamuri S et al (2016) TRAF3IP2 mediates atherosclerotic plaque development and vulnerability in ApoE(-/-) mice. Atherosclerosis 252:153–160

    Article  PubMed  CAS  Google Scholar 

  51. Alt EU et al (2018) TRAF3IP2, a novel therapeutic target in glioblastoma multiforme. Oncotarget 9(51):29772–29788

    Article  PubMed  PubMed Central  Google Scholar 

  52. Hu HH et al (2018) New insights into TGF-β/Smad signaling in tissue fibrosis. Chem Biol Interact 292:76–83

    Article  PubMed  CAS  Google Scholar 

  53. Krueger JG et al (2024) IL-23 past, present, and future: a roadmap to advancing IL-23 science and therapy. Front Immunol 15:1331217

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Cooney LA et al (2011) Sensitivity and resistance to regulation by IL-4 during Th17 maturation. J Immunol 187(9):4440–4450

    Article  PubMed  CAS  Google Scholar 

  55. Tanaka Y et al (2022) Janus kinase-targeting therapies in rheumatology: a mechanisms-based approach. Nat Rev Rheumatol 18(3):133–145

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Catlett IM et al (2023) First-in-human study of deucravacitinib: a selective, potent, allosteric small-molecule inhibitor of tyrosine kinase 2. Clin Transl Sci 16(1):151–164

    Article  PubMed  CAS  Google Scholar 

  57. Sakai R et al (2024) Increased risk of cardiovascular events under the treatments with Janus kinase inhibitors versus biological disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: a retrospective longitudinal population-based study using the Japanese health insurance database. RMD Open, 10(2)

  58. Opdam MAA et al (2024) Higher infection risk for JAK inhibitors tofacitinib and baricitinib compared to subcutaneous biological DMARDs. Clin Rheumatol 43(6):2133–2138

    Article  PubMed  CAS  Google Scholar 

  59. Luk K, Fakhoury J, Ozog D (2022) Nonresponse and progression of diffuse keloids to Dupilumab Therapy. J Drugs Dermatol 21(2):197–199

    Article  PubMed  Google Scholar 

  60. Tirgan MH, Uitto J (2022) Lack of efficacy of dupilumab in the treatment of keloid disorder. J Eur Acad Dermatol Venereol 36(2):e120–e122

    Article  PubMed  CAS  Google Scholar 

  61. Min MS et al (2023) Successful treatment of keloids and hypertrophic scars with systemic and Intralesional Dupilumab. J Drugs Dermatol 22(12):1220–1222

    Article  PubMed  Google Scholar 

  62. Wittmer A, Finklea L, Joseph J (2023) Effects of dupilumab on keloid stabilization and prevention. JAAD Case Rep 37:103–105

    Article  PubMed  PubMed Central  Google Scholar 

  63. Wong AJS, Song EJ (2021) Dupilumab as an adjuvant treatment for keloid-associated symptoms. JAAD Case Rep 13:73–74

    Article  PubMed  PubMed Central  Google Scholar 

  64. Diaz A et al (2020) Keloid lesions show increased IL-4/IL-13 signaling and respond to Th2-targeting dupilumab therapy. J Eur Acad Dermatol Venereol 34(4):e161–e164

    Article  PubMed  CAS  Google Scholar 

  65. ClinicalTrials.gov. NCT04988022: Study to Evaluate the Efficacy and Safety of Dupilumab in Participants With Keloid (2024) 2024/06/26] ; https://clinicaltrials.gov/study/NCT04988022?cond=Keloid%20dupilumab&rank=1

  66. Chen JY et al (2023) An Open-Label, uncontrolled, single-arm clinical trial of Tofacitinib, an oral JAK1 and JAK3 kinase inhibitor, in Chinese patients with Keloid. Dermatology 239(5):818–827

    Article  PubMed  CAS  Google Scholar 

  67. Ogawa R (2022) The most current algorithms for the Treatment and Prevention of Hypertrophic Scars and keloids: a 2020 update of the algorithms published 10 years ago. Plast Reconstr Surg 149(1):79e–94e

    Article  PubMed  CAS  Google Scholar 

  68. Ogawa R et al (2019) Surgical excision and postoperative radiotherapy for keloids. Scars Burn Heal 5:2059513119891113

    PubMed  PubMed Central  Google Scholar 

  69. Chike-Obi CJ, Cole PD, Brissett AE (2009) Keloids: pathogenesis, clinical features, and management. Semin Plast Surg 23(3):178–184

    Article  PubMed  PubMed Central  Google Scholar 

  70. Drugs.com. Cosentyx: History (2024) /06/26] ; https://www.drugs.com/history/cosentyx.html

  71. Drugs.com. Taltz: History (2024) /06/26] ; https://www.drugs.com/history/taltz.html

  72. Drugs.com. Bimzelx: History (2024) /06/26] ; https://www.drugs.com/history/bimzelx.html

  73. Drugs.com. Siliq: History (2024) /06/26] ; https://www.drugs.com/history/siliq.html

  74. Drugs.com. Stelara: History (2024) /06/26] ; https://www.drugs.com/history/stelara.html

  75. Drugs.com. Tremfya: History (2024) /06/26] ; https://www.drugs.com/history/tremfya.html

  76. Drugs.com. Ilumya: History (2024) /06/26] ; https://www.drugs.com/history/ilumya.html

  77. Drugs.com. Skyrizi: History (2024) /06/26] ; https://www.drugs.com/history/skyrizi.html

  78. Drugs.com. Actemra: History (2024) /06/27] ; https://www.drugs.com/history/actemra.html

  79. Drugs.com. Kevzara: History (2024) /06/27] ; https://www.drugs.com/history/kevzara.html

  80. Drugs.com. Enspryng: History (2024) /06/27] ; https://www.drugs.com/history/enspryng.html

  81. Drugs.com. Sylvant: History (2024) /06/27] ; https://www.drugs.com/history/sylvant.html

  82. Drugs.com. Xeljanz: History (2024) /06/27] ; https://www.drugs.com/history/xeljanz.html

  83. Drugs.com. Olumiant: History (2024) /06/27] ; https://www.drugs.com/history/olumiant.html

  84. Drugs.com. Jakafi: History (2024) /06/27] ; https://www.drugs.com/history/jakafi.html

  85. Drugs.com. Opzelura: History (2024) /06/27] ; https://www.drugs.com/history/opzelura.html

  86. Drugs.com. Leqselvi: History (2024) /08/04] ; https://www.drugs.com/history/leqselvi.html

  87. Drugs.com. Rinvoq: History (2024) /06/27] ; https://www.drugs.com/history/rinvoq.html

  88. Drugs.com. Cibinqo: History (2024) /06/27] ; https://www.drugs.com/history/cibinqo.html

  89. Drugs.com. Sotyktu: History (2024) /06/27] ; https://www.drugs.com/history/sotyktu.html

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Acknowledgements

DB performed the literature search and wrote the main manuscript. DB and JYW reviewed the studies independently. JYW, AC, KZ, MK, PP, LJ, MC, and EA helped to review the manuscript. JJ helped edit/review the final manuscript. All authors reviewed and approved the final manuscript.

Funding

No funding has been received for this article. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the U.S. Department of Veterans Affairs or the United States Government.

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Authors and Affiliations

  1. Dermatology Service, Veterans Affairs New York Harbor Healthcare System - Brooklyn Campus, Brooklyn, NY, USA

    David Bitterman, Jennifer Y. Wang, Alexia Collins, Kayla Zafar, Margaret Kabakova, Paras Patel, Lucie Joerg, Marc Cohen, Evan Austin & Jared Jagdeo

  2. New York Medical College, Valhalla, NY, USA

    David Bitterman

  3. Department of Dermatology, State University of New York, Downstate Health Sciences University, Brooklyn, NY, USA

    Jennifer Y. Wang, Alexia Collins, Margaret Kabakova, Marc Cohen, Evan Austin & Jared Jagdeo

  4. St. George’s University School of Medicine, Grenada, West Indies, True Blue, Grenada

    Kayla Zafar

  5. Rowan University School of Osteopathic Medicine, Stratford, NJ, USA

    Paras Patel

  6. Albany Medical College, Albany, NY, USA

    Lucie Joerg

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DB performed the literature search and wrote the main manuscript. DB and JYW reviewed the studies independently. DB prepared Tables 1 and 2. DB, AC, and JJ prepared Figs. 1, 2 and 3. JYW, AC, KZ, MK, PP, LJ, MC, and EA helped to review the manuscript. JJ helped edit/review the final manuscript. All authors reviewed and approved the final manuscript.

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Correspondence to Jared Jagdeo.

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Bitterman, D., Wang, J.Y., Collins, A. et al. The role of IL-17 and Th17 cells in keloid pathogenesis. Arch Dermatol Res 316, 626 (2024). https://doi.org/10.1007/s00403-024-03352-y

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