Identification and subtype analysis of IL-17 related diagnostic biomarkers in atopic dermatitis based on WGCNA and machine learning
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disease with heterogeneous immune dysregulation. Although interleukin-17 (IL-17) signaling is implicated in AD, IL-17-related diagnostic biomarkers and molecular subtypes remain unclear. This study aimed to identify IL-17-associated biomarkers, characterize immune infiltration and subtypes, and explore upstream regulatory mechanisms.
Gene expression datasets (GSE121212, GSE6012) were acquired from the Gene Expression Omnibus database, and an IL-17-related gene set was collected from the Gene Set Enrichment Analysis website (GSEA)(http://www.gsea-msigdb.org/gsea/msigdb/search.jsp). Differential expression (limma) and Weighted Gene Co-expression Network Analysis were integrated to identify candidate genes, followed by feature selection using Least Absolute Shrinkage and Selection Operator and random forest. We evaluated immune cell infiltration by applying the CIBERSORT algorithm alongside single-sample Gene Set Enrichment Analysis. GSEA was applied to investigate underlying biological processes. AD patients were clustered into subtypes relying on IL-17 scores using ssGSEA.
Our integrated analysis identified IL4R and PRSS22 as key IL-17-related diagnostic biomarkers for AD, demonstrating excellent diagnostic accuracy across both training and validation cohorts. Immune-infiltration analyses revealed altered immune-cell composition and correlations observed between the identified biomarkers and specific immune cells. Two distinct AD subtypes were identified based on IL-17 scores, exhibiting immune infiltration patterns and enriched biological pathways. A ceRNA network highlighted potential regulatory mechanisms involving these biomarkers.
IL4R and PRSS22 are robust IL-17-related diagnostic biomarkers for AD, with high predictive power across cohorts. Immune infiltration profiling and IL-17 score-based subtyping reveal AD heterogeneity. These findings provide a foundation for improved diagnosis, molecular stratification, and potential therapeutic targeting in AD.
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2. Lobefaro F, Gualdi G, Di Nuzzo S, Amerio P, et al. Atopic dermatitis: Clinical aspects and unmet needs. Biomedicines. 2022;10(11).
3. Chovatiya R, Silverberg JI. The heterogeneity of atopic dermatitis. J Drugs Dermatol. 2022;21(2):172-6.
4. Hurel Barroso M, Oliveira Rodrigues Valle S, Duarte Dortas Junior S, Raggio Luiz R, Lupi O, et al. Sleep and quality of life in adults with atopic dermatitis: cross sectional study. Eur Ann Allergy Clin Immunol. 2024.
5. Manjelievskaia J, Boytsov N, Brouillette MA, Onyekwere U, Pierce E, Goldblum O, et al. The direct and indirect costs of adult atopic dermatitis. J Manag Care Spec Pharm. 2021;27(10):1416-25.
6. Boothe WD, Tarbox JA, Tarbox MB, et al. Atopic dermatitis: pathophysiology. Adv Exp Med Biol. 2024;1447:21-35.
7. Gavrilova T. Immune dysregulation in the pathogenesis of atopic dermatitis. Dermatitis. 2018;29(2):57-62.
8. Czarnowicki T, Krueger JG, Guttman-Yassky E. Skin barrier and immune dysregulation in atopic dermatitis: an evolving story with important clinical implications. J Allergy Clin Immunol Pract. 2014;2(4):371-379; quiz 380-1.
9. Afshari M, Kolackova M, Rosecka M, Čelakovská J, Krejsek J, et al. Unraveling the skin; a comprehensive review of atopic dermatitis, current understanding, and approaches. Front Immunol. 2024;15:1361005.
10. Dhingra N, Guttman-Yassky E. A possible role for IL-17A in establishing Th2 inflammation in murine models of atopic dermatitis. J Invest Dermatol. 2014;134(8):2071-4.
11. Meesters LD, Roubroeks JAY, Gerritsen A, Velthuijs N, Klijnhout JA, Laberthonnière C, et al. Dissecting key contributions of T(H)2 and T(H)17 cytokines to atopic dermatitis pathophysiology. J Allergy Clin Immunol. 2025;156(3):690-704.
12. Rothenberg-Lausell C, Bar J, Del Duca E, Guttman-Yassky E, et al. Diversity of atopic dermatitis and selection of immune targets. Ann Allergy Asthma Immunol. 2024;132(2):177-86.
13. Libon F, Caron J, Nikkels AF, et al. Biomarkers in atopic dermatitis. Dermatol Ther. 2024;14(7):1729-38.
14. Mastraftsi S, Vrioni G, Bakakis M, Nicolaidou E, Rigopoulos D, Stratigos AJ, et al. Atopic dermatitis: striving for reliable biomarkers. J Clin Med. 2022;11(16).
15. Sims JT, Chang CY, Higgs RE, Engle SM, Liu Y, Sissons SE, et al. Insights into adult atopic dermatitis heterogeneity derived from circulating biomarker profiling in patients with moderate-to-severe disease. Exp Dermatol. 2021;30(11):1650-61.
16. Akhter S, Tasnim FM, Islam MN, Rauf A, Mitra S, Emran TB, et al. Role of Th17 and IL-17 cytokines on inflammatory and auto-immune diseases. Curr Pharm Des. 2023;29(26):2078-90.
17. Mills KHG. IL-17 and IL-17-producing cells in protection versus pathology. Nat Rev Immunol. 2023;23(1):38-54.
18. Hassan Z, Luvsannyam E, Patel D, Nukala S, Puvvada SR, Hamid P, et al. Review of prominent cytokines as superior therapeutic targets for moderate-to-severe atopic dermatitis. Cureus. 2020;12(8):e9901.
19. Furue M, Furue K, Tsuji G, Nakahara T. Interleukin-17A and keratinocytes in psoriasis. Int J Mol Sci. 2020;21(4).
20. Haertlé J, Kienlin P, Begemann G, Werfel T, Roesner LM. Inhibition of IL-17 ameliorates keratinocyte-borne cytokine responses in an in vitro model for house-dust-mite triggered atopic dermatitis. Sci Rep. 2023;13(1):16628.
21. Dong W, Gu X, Li J, Zhuang Z. Characterization of immune landscape and prognostic value of IL-17-related signature in invasive breast cancer. Transl Cancer Res. 2025;14(2):907-29.
22. Schuler CF, Tsoi LC, Billi AC, Harms PW, Weidinger S, Gudjonsson JE, et al. Genetic and immunological pathogenesis of atopic dermatitis. J Invest Dermatol. 2024;144(5):954-68.
23. David E, Czarnowicki T. The pathogenetic role of Th17 immune response in atopic dermatitis. Curr Opin Allergy Clin Immunol. 2023;23(5):446-53.
24. Berdyshev E, Goleva E, Bronova I, Dyjack N, Rios C, Jung J, et al. Lipid abnormalities in atopic skin are driven by type 2 cytokines. JCI Insight. 2018;3(4).
25. Zuo W, Yue Z, Xu S, Sun CH, Zou XF, Ma J, et al. Emerging trends and research hotspots in the relationship between mast cells and atopic dermatitis: a bibliometric and visualized analysis. Skin Res Technol. 2024;30(9):e70053.
26. Junttila IS. Tuning the cytokine responses: an update on interleukin (IL)-4 and IL-13 receptor complexes. Front Immunol. 2018;9:888.
27. Kim J, Kim BE, Leung DYM. Pathophysiology of atopic dermatitis: clinical implications. Allergy Asthma Proc. 2019;40(2):84-92.
28. Leyva-Castillo JM, McGurk A, Strakosha M, Vega-Mendoza D, Smith SEM, Stafstrom K, et al. IL-4 receptor alpha blockade dampens allergic inflammation and upregulates IL-17A expression to promote S. aureus clearance in antigen sensitized mouse skin. J Allergy Clin Immunol. 2023;152(4):907-15.
29. Song L, Li H, Ma RR, Liu S, Zhang GH, Guo XY, et al. E2F1-initiated transcription of PRSS22 promotes breast cancer metastasis by cleaving ANXA1 and activating FPR2/ERK signaling pathway. Cell Death Dis. 2022;13(11):982.
30. Fan M, Fan X, Lai Y, Chen J, Peng Y, Peng Y, et al. Protease-activated receptor 2 in inflammatory skin disease: current evidence and future perspectives. Front Immunol. 2024;15:1448952.
31. Barr TP, Garzia C, Guha S, Fletcher EK, Nguyen N, Wieschhaus AJ, et al. PAR2 pepducin-based suppression of inflammation and itch in atopic dermatitis models. J Invest Dermatol. 2019;139(2):412-21.
32. Torres T, Mendes-Bastos P, Cruz MJ, Duarte B, Filipe P, Lopes MJP, et al. Interleukin-4 and atopic dermatitis: why does it matter? A narrative review. Dermatol Ther. 2025;15(3):579-97.
33. Yu L, Li L. Potential biomarkers of atopic dermatitis. Front Med. 2022;9:1028694.
34. Renert-Yuval Y, Thyssen JP, Bissonnette R, Bieber T, Kabashima K, Hijnen D, et al. Biomarkers in atopic dermatitis—a review on behalf of the International Eczema Council. J Allergy Clin Immunol. 2021;147(4):1174-1190.e1.
35. Fyhrquist N, Yang Y, Karisola P, Alenius H, et al. Endotypes of atopic dermatitis. J Allergy Clin Immunol. 2025;156(1):24-40.e4.
36. Makowska K, Nowaczyk J, Blicharz L, Waśkiel-Burnat A, Czuwara J, Olszewska M, et al. Immunopathogenesis of atopic dermatitis: focus on interleukins as disease drivers and therapeutic targets for novel treatments. Int J Mol Sci. 2023;24(1).
37. Sroka-Tomaszewska J, Trzeciak M. Molecular mechanisms of atopic dermatitis pathogenesis. Int J Mol Sci. 2021;22(8).
38. Vercelli D. IL-4 and dendritic cells in atopic dermatitis: old dogs learn new tricks. J Allergy Clin Immunol. 2024;154(6):1419-21.
39. Xu K, Wang L, Lin M, He G. Update on protease-activated receptor 2 in inflammatory and autoimmune dermatological diseases. Front Immunol. 2024;15:1449126.
40. Voss M, Kotrba J, Gaffal E, Katsoulis-Dimitriou K, Dudeck A, et al. Mast cells in the skin: defenders of integrity or offenders in inflammation? Int J Mol Sci. 2021;22(9).
41. Fujita H, Shemer A, Suárez-Fariñas M, Johnson-Huang LM, Tintle S, Cardinale I, et al. Lesional dendritic cells in patients with chronic atopic dermatitis and psoriasis exhibit parallel ability to activate T-cell subsets. J Allergy Clin Immunol. 2011;128(3):574-582.e1-12.
42. Wong GW, Foster PS, Yasuda S, et al. Human tryptase epsilon (PRSS22), a new member of the chromosome 16p13.3 family of human serine proteases expressed in airway epithelial cells. J Biol Chem. 2001;276(49):49169–78.
43. Peng S, Chen M, Yin M, Feng H. Identifying the potential therapeutic targets for atopic dermatitis through the immune infiltration analysis and construction of a ceRNA network. Clin Cosmet Investig Dermatol. 2021;14:437-53.
44. Dopytalska K, Czaplicka A, Szymańska E, et al.; The Essential Role of microRNAs in Inflammatory and Autoimmune Skin Diseases-A Review. Int J Mol Sci, 2023;24(11):9130.
45. Amicone L, Marchetti A, Cicchini C; The lncRNA HOTAIR: a pleiotropic regulator of epithelial cell plasticity. J Exp Clin Cancer Res, 2023;42(1):147.
2. Lobefaro F, Gualdi G, Di Nuzzo S, Amerio P, et al. Atopic dermatitis: Clinical aspects and unmet needs. Biomedicines. 2022;10(11).
3. Chovatiya R, Silverberg JI. The heterogeneity of atopic dermatitis. J Drugs Dermatol. 2022;21(2):172-6.
4. Hurel Barroso M, Oliveira Rodrigues Valle S, Duarte Dortas Junior S, Raggio Luiz R, Lupi O, et al. Sleep and quality of life in adults with atopic dermatitis: cross sectional study. Eur Ann Allergy Clin Immunol. 2024.
5. Manjelievskaia J, Boytsov N, Brouillette MA, Onyekwere U, Pierce E, Goldblum O, et al. The direct and indirect costs of adult atopic dermatitis. J Manag Care Spec Pharm. 2021;27(10):1416-25.
6. Boothe WD, Tarbox JA, Tarbox MB, et al. Atopic dermatitis: pathophysiology. Adv Exp Med Biol. 2024;1447:21-35.
7. Gavrilova T. Immune dysregulation in the pathogenesis of atopic dermatitis. Dermatitis. 2018;29(2):57-62.
8. Czarnowicki T, Krueger JG, Guttman-Yassky E. Skin barrier and immune dysregulation in atopic dermatitis: an evolving story with important clinical implications. J Allergy Clin Immunol Pract. 2014;2(4):371-379; quiz 380-1.
9. Afshari M, Kolackova M, Rosecka M, Čelakovská J, Krejsek J, et al. Unraveling the skin; a comprehensive review of atopic dermatitis, current understanding, and approaches. Front Immunol. 2024;15:1361005.
10. Dhingra N, Guttman-Yassky E. A possible role for IL-17A in establishing Th2 inflammation in murine models of atopic dermatitis. J Invest Dermatol. 2014;134(8):2071-4.
11. Meesters LD, Roubroeks JAY, Gerritsen A, Velthuijs N, Klijnhout JA, Laberthonnière C, et al. Dissecting key contributions of T(H)2 and T(H)17 cytokines to atopic dermatitis pathophysiology. J Allergy Clin Immunol. 2025;156(3):690-704.
12. Rothenberg-Lausell C, Bar J, Del Duca E, Guttman-Yassky E, et al. Diversity of atopic dermatitis and selection of immune targets. Ann Allergy Asthma Immunol. 2024;132(2):177-86.
13. Libon F, Caron J, Nikkels AF, et al. Biomarkers in atopic dermatitis. Dermatol Ther. 2024;14(7):1729-38.
14. Mastraftsi S, Vrioni G, Bakakis M, Nicolaidou E, Rigopoulos D, Stratigos AJ, et al. Atopic dermatitis: striving for reliable biomarkers. J Clin Med. 2022;11(16).
15. Sims JT, Chang CY, Higgs RE, Engle SM, Liu Y, Sissons SE, et al. Insights into adult atopic dermatitis heterogeneity derived from circulating biomarker profiling in patients with moderate-to-severe disease. Exp Dermatol. 2021;30(11):1650-61.
16. Akhter S, Tasnim FM, Islam MN, Rauf A, Mitra S, Emran TB, et al. Role of Th17 and IL-17 cytokines on inflammatory and auto-immune diseases. Curr Pharm Des. 2023;29(26):2078-90.
17. Mills KHG. IL-17 and IL-17-producing cells in protection versus pathology. Nat Rev Immunol. 2023;23(1):38-54.
18. Hassan Z, Luvsannyam E, Patel D, Nukala S, Puvvada SR, Hamid P, et al. Review of prominent cytokines as superior therapeutic targets for moderate-to-severe atopic dermatitis. Cureus. 2020;12(8):e9901.
19. Furue M, Furue K, Tsuji G, Nakahara T. Interleukin-17A and keratinocytes in psoriasis. Int J Mol Sci. 2020;21(4).
20. Haertlé J, Kienlin P, Begemann G, Werfel T, Roesner LM. Inhibition of IL-17 ameliorates keratinocyte-borne cytokine responses in an in vitro model for house-dust-mite triggered atopic dermatitis. Sci Rep. 2023;13(1):16628.
21. Dong W, Gu X, Li J, Zhuang Z. Characterization of immune landscape and prognostic value of IL-17-related signature in invasive breast cancer. Transl Cancer Res. 2025;14(2):907-29.
22. Schuler CF, Tsoi LC, Billi AC, Harms PW, Weidinger S, Gudjonsson JE, et al. Genetic and immunological pathogenesis of atopic dermatitis. J Invest Dermatol. 2024;144(5):954-68.
23. David E, Czarnowicki T. The pathogenetic role of Th17 immune response in atopic dermatitis. Curr Opin Allergy Clin Immunol. 2023;23(5):446-53.
24. Berdyshev E, Goleva E, Bronova I, Dyjack N, Rios C, Jung J, et al. Lipid abnormalities in atopic skin are driven by type 2 cytokines. JCI Insight. 2018;3(4).
25. Zuo W, Yue Z, Xu S, Sun CH, Zou XF, Ma J, et al. Emerging trends and research hotspots in the relationship between mast cells and atopic dermatitis: a bibliometric and visualized analysis. Skin Res Technol. 2024;30(9):e70053.
26. Junttila IS. Tuning the cytokine responses: an update on interleukin (IL)-4 and IL-13 receptor complexes. Front Immunol. 2018;9:888.
27. Kim J, Kim BE, Leung DYM. Pathophysiology of atopic dermatitis: clinical implications. Allergy Asthma Proc. 2019;40(2):84-92.
28. Leyva-Castillo JM, McGurk A, Strakosha M, Vega-Mendoza D, Smith SEM, Stafstrom K, et al. IL-4 receptor alpha blockade dampens allergic inflammation and upregulates IL-17A expression to promote S. aureus clearance in antigen sensitized mouse skin. J Allergy Clin Immunol. 2023;152(4):907-15.
29. Song L, Li H, Ma RR, Liu S, Zhang GH, Guo XY, et al. E2F1-initiated transcription of PRSS22 promotes breast cancer metastasis by cleaving ANXA1 and activating FPR2/ERK signaling pathway. Cell Death Dis. 2022;13(11):982.
30. Fan M, Fan X, Lai Y, Chen J, Peng Y, Peng Y, et al. Protease-activated receptor 2 in inflammatory skin disease: current evidence and future perspectives. Front Immunol. 2024;15:1448952.
31. Barr TP, Garzia C, Guha S, Fletcher EK, Nguyen N, Wieschhaus AJ, et al. PAR2 pepducin-based suppression of inflammation and itch in atopic dermatitis models. J Invest Dermatol. 2019;139(2):412-21.
32. Torres T, Mendes-Bastos P, Cruz MJ, Duarte B, Filipe P, Lopes MJP, et al. Interleukin-4 and atopic dermatitis: why does it matter? A narrative review. Dermatol Ther. 2025;15(3):579-97.
33. Yu L, Li L. Potential biomarkers of atopic dermatitis. Front Med. 2022;9:1028694.
34. Renert-Yuval Y, Thyssen JP, Bissonnette R, Bieber T, Kabashima K, Hijnen D, et al. Biomarkers in atopic dermatitis—a review on behalf of the International Eczema Council. J Allergy Clin Immunol. 2021;147(4):1174-1190.e1.
35. Fyhrquist N, Yang Y, Karisola P, Alenius H, et al. Endotypes of atopic dermatitis. J Allergy Clin Immunol. 2025;156(1):24-40.e4.
36. Makowska K, Nowaczyk J, Blicharz L, Waśkiel-Burnat A, Czuwara J, Olszewska M, et al. Immunopathogenesis of atopic dermatitis: focus on interleukins as disease drivers and therapeutic targets for novel treatments. Int J Mol Sci. 2023;24(1).
37. Sroka-Tomaszewska J, Trzeciak M. Molecular mechanisms of atopic dermatitis pathogenesis. Int J Mol Sci. 2021;22(8).
38. Vercelli D. IL-4 and dendritic cells in atopic dermatitis: old dogs learn new tricks. J Allergy Clin Immunol. 2024;154(6):1419-21.
39. Xu K, Wang L, Lin M, He G. Update on protease-activated receptor 2 in inflammatory and autoimmune dermatological diseases. Front Immunol. 2024;15:1449126.
40. Voss M, Kotrba J, Gaffal E, Katsoulis-Dimitriou K, Dudeck A, et al. Mast cells in the skin: defenders of integrity or offenders in inflammation? Int J Mol Sci. 2021;22(9).
41. Fujita H, Shemer A, Suárez-Fariñas M, Johnson-Huang LM, Tintle S, Cardinale I, et al. Lesional dendritic cells in patients with chronic atopic dermatitis and psoriasis exhibit parallel ability to activate T-cell subsets. J Allergy Clin Immunol. 2011;128(3):574-582.e1-12.
42. Wong GW, Foster PS, Yasuda S, et al. Human tryptase epsilon (PRSS22), a new member of the chromosome 16p13.3 family of human serine proteases expressed in airway epithelial cells. J Biol Chem. 2001;276(49):49169–78.
43. Peng S, Chen M, Yin M, Feng H. Identifying the potential therapeutic targets for atopic dermatitis through the immune infiltration analysis and construction of a ceRNA network. Clin Cosmet Investig Dermatol. 2021;14:437-53.
44. Dopytalska K, Czaplicka A, Szymańska E, et al.; The Essential Role of microRNAs in Inflammatory and Autoimmune Skin Diseases-A Review. Int J Mol Sci, 2023;24(11):9130.
45. Amicone L, Marchetti A, Cicchini C; The lncRNA HOTAIR: a pleiotropic regulator of epithelial cell plasticity. J Exp Clin Cancer Res, 2023;42(1):147.
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How to Cite
1.
Mei C, Xu C, Yu Z, Shen L. Identification and subtype analysis of IL-17 related diagnostic biomarkers in atopic dermatitis based on WGCNA and machine learning. Iran J Allergy Asthma Immunol. 2026;:1-17.
