Causal effects of inflammatory cytokines on hemangioma mediated by blood metabolites: a two-step Mendelian randomization study
Abstract
Background: Hemangioma is the most prevalent infantile vascular tumor. The state of inflammation and metabolism may contribute to the occurrence and development of hemangioma, but their causal relationships have not been clearly elucidated. In this study, via Mendelian randomization (MR) analysis, we aimed to investigate the causal effect of inflammatory cytokines and blood metabolites on hemangioma, and to explore the potential mediating role of metabolites.
Methods: Applying large-scale genome-wide association studies (GWAS) dataset, we applied two-sample MR to infer causal relationships among 91 inflammatory cytokines, 1091 blood metabolites and 309 metabolite ratios，and hemangioma. In addition, a two-step MR was used to assess the potential mediating role of metabolites. Functional enrichment was also performed to explore the biological pathways involved.
Results: 9 cytokines exhibited significant causal effects on hemangioma. Cytokines such as CCL20, IFN-γ, Eotaxin and TRANCE were associated with an increased risk, while IL12B, CXCL11, TGF-α, OSM and IL17A were inversely associated. Additionally, 52 blood metabolites and metabolite-ratios were discovered to have causal effects on hemangioma. 18 metabolites and metabolite-ratios were associated with an elevated risk of hemangioma, whereas 34 metabolites and metabolite-ratios appeared to be protective factors. Mediation analysis further identified specific metabolites, such as Gamma-glutamylvaline, as mediators in cytokine-hemangioma pathways, suggesting that they might modulate cytokine-driven tumorigenesis.
Conclusion: As the first MR study focused on hemangioma, we identified key cytokines and metabolites which might exert a causal effect on hemangioma, with several metabolites functioning as intermediators in cytokine-induced tumorigenesis process. The complex interaction between inflammation and metabolism in hemangioma was revealed, laying a foundation for future studies to explore potential targeted treatments.
References
2. Mitra R, Fitzsimons HL, Hale T, Tan ST, Gray C, White M. Recent advances in understanding the molecular basis of infantile haemangioma development. Brit J Dermatol 2024; 191(5): 661-9.
3. Krowchuk DP, Frieden IJ, Mancini AJ, Darrow DH, Blei F, Greene AK, et al. Clinical Practice Guideline for the Management of Infantile Hemangiomas. Pediatrics 2019; 143(1): e20183475.
4. Xiang S, Gong X, Qiu T, Zhou J, Yang K, Lan Y, et al. Insights into the mechanisms of angiogenesis in infantile hemangioma. Biomed Pharmacother 2024; 178(117181.
5. de Visser KE, Joyce JA. The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth. Cancer Cell 2023; 41(3): 374-403.
6. Denk D, Greten FR. Inflammation: the incubator of the tumor microenvironment. Trends Cancer 2022; 8(11): 901-14.
7. Du W, Ren L, Hamblin MH, Fan Y. Endothelial Cell Glucose Metabolism and Angiogenesis. Biomedicines 2021; 9(2): 147.
8. Rohlenova K, Veys K, Miranda-Santos I, De Bock K, Carmeliet P. Endothelial Cell Metabolism in Health and Disease. Trends Cell Biol 2018; 28(3): 224-36.
9. Treps L, Conradi LC, Harjes U, Carmeliet P. Manipulating Angiogenesis by Targeting Endothelial Metabolism: Hitting the Engine Rather than the Drivers-A New Perspective? Pharmacol Rev 2016; 68(3): 872-87.
10. Skrivankova VW, Richmond RC, Woolf B, Davies NM, Swanson SA, VanderWeele TJ, et al. Strengthening the reporting of observational studies in epidemiology using mendelian randomisation (STROBE-MR): explanation and elaboration. Bmj-Brit Med J 2021; 375: n2233.
11. Skrivankova VW, Richmond RC, Woolf B, Yarmolinsky J, Davies NM, Swanson SA, et al. Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization: The STROBE-MR Statement. Jama-J Am Med Assoc 2021; 326(16): 1614-21.
12. Zhao JH, Stacey D, Eriksson N, Macdonald-Dunlop E, Hedman AK, Kalnapenkis A, et al. Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets. Nat Immunol 2023; 24(9): 1540-51.
13. Chen Y, Lu T, Pettersson-Kymmer U, Stewart ID, Butler-Laporte G, Nakanishi T, et al. Genomic atlas of the plasma metabolome prioritizes metabolites implicated in human diseases. Nat Genet 2023; 55(1): 44-53.
14. Kurki MI, Karjalainen J, Palta P, Sipila TP, Kristiansson K, Donner KM, et al. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature 2023; 613(7944): 508-18.
15. Pang Z, Lu Y, Zhou G, Hui F, Xu L, Viau C, et al. MetaboAnalyst 6.0: towards a unified platform for metabolomics data processing, analysis and interpretation. Nucleic Acids Res 2024; 52(W1): W398-406.
16. Asosingh K, Vasanji A, Tipton A, Queisser K, Wanner N, Janocha A, et al. Eotaxin-Rich Proangiogenic Hematopoietic Progenitor Cells and CCR3+ Endothelium in the Atopic Asthmatic Response. J Immunol 2016; 196(5): 2377-87.
17. Salcedo R, Young HA, Ponce ML, Ward JM, Kleinman HK, Murphy WJ, et al. Eotaxin (CCL11) induces in vivo angiogenic responses by human CCR3+ endothelial cells. J Immunol 2001; 166(12): 7571-8.
18. Hippe A, Braun SA, Olah P, Gerber PA, Schorr A, Seeliger S, et al. EGFR/Ras-induced CCL20 production modulates the tumour microenvironment. Brit J Cancer 2020; 123(6): 942-54.
19. Min JK, Kim YM, Kim YM, Kim EC, Gho YS, Kang IJ, et al. Vascular endothelial growth factor up-regulates expression of receptor activator of NF-kappa B (RANK) in endothelial cells. Concomitant increase of angiogenic responses to RANK ligand. J Biol Chem 2003; 278(41): 39548-57.
20. Kim YM, Kim YM, Lee YM, Kim HS, Kim JD, Choi Y, et al. TNF-related activation-induced cytokine (TRANCE) induces angiogenesis through the activation of Src and phospholipase C (PLC) in human endothelial cells. J Biol Chem 2002; 277(9): 6799-805.
21. Sakata M, Kunimoto K, Kawaguchi A, Inaba Y, Kaminaka C, Yamamoto Y, et al. Analysis of cytokine profiles in sera of single and multiple infantile hemangioma. J Dermatol 2023; 50(7): 906-11.
22. Peng Q, Liu W, Zhou F, Wang Y, Ji Y. An experimental study on the therapy of infantile hemangioma with recombinant interferon gamma. J Pediatr Surg 2011; 46(3): 496-501.
23. Airoldi I, Ribatti D. Regulation of angiostatic chemokines driven by IL-12 and IL-27 in human tumors. J Leukocyte Biol 2011; 90(5): 875-82.
24. Lee J, Goeckel ME, Levitas A, Colijn S, Shin J, Hindes A, et al. CXCR3-CXCL11 Signaling Restricts Angiogenesis and Promotes Pericyte Recruitment. Arterioscl Throm Vas 2024; 44(12): 2577-95.
25. Wu KQ, Muratore CS, So EY, Sun C, Dubielecka PM, Reginato AM, et al. M1 Macrophage-Induced Endothelial-to-Mesenchymal Transition Promotes Infantile Hemangioma Regression. Am J Pathol 2017; 187(9): 2102-11.
26. Guo S, Li ZZ, Gong J, Xiang M, Zhang P, Zhao GN, et al. Oncostatin M Confers Neuroprotection against Ischemic Stroke. J Neurosci 2015; 35(34): 12047-62.
27. Zhang X, Zhu D, Wei L, Zhao Z, Qi X, Li Z, et al. OSM Enhances Angiogenesis and Improves Cardiac Function after Myocardial Infarction. Biomed Res Int 2015; 2015: 317905.
28. van Keulen D, Pouwer MG, Pasterkamp G, van Gool AJ, Sollewijn GM, Princen H, et al. Inflammatory cytokine oncostatin M induces endothelial activation in macro- and microvascular endothelial cells and in APOE*3Leiden.CETP mice. Plos One 2018; 13(10): e0204911.
29. Wang R, Lou X, Feng G, Chen J, Zhu L, Liu X, et al. IL-17A-stimulated endothelial fatty acid beta-oxidation promotes tumor angiogenesis. Life Sci 2019; 229: 46-56.
30. Taylor BE, Lee CA, Zapadka TE, Zhou AY, Barber KG, Taylor Z, et al. IL-17A Enhances Retinal Neovascularization. Int J Mol Sci 2023; 24(2): 1747.
31. Gatsiou A, Sopova K, Tselepis A, Stellos K. Interleukin-17A Triggers the Release of Platelet-Derived Factors Driving Vascular Endothelial Cells toward a Pro-Angiogenic State. Cells-Basel 2021; 10(8): 1855.
32. Li N, Luo R, Zhang W, Wu Y, Hu C, Liu M, et al. IL-17A promotes endothelial cell senescence by up-regulating the expression of FTO through activating JNK signal pathway. Biogerontology 2023; 24(1): 99-110.
33. Li X, Kumar A, Carmeliet P. Metabolic Pathways Fueling the Endothelial Cell Drive. Annu Rev Physiol 2019; 81: 483-503.
34. De Bock K, Georgiadou M, Schoors S, Kuchnio A, Wong BW, Cantelmo AR, et al. Role of PFKFB3-driven glycolysis in vessel sprouting. Cell 2013; 154(3): 651-63.
35. Yang K, Li X, Qiu T, Zhou J, Gong X, Lan Y, et al. Effects of propranolol on glucose metabolism in hemangioma-derived endothelial cells. Biochem Pharmacol 2023; 218: 115922.
Copyright (c) 2025 Fan Yu, Yuanhe You, Zhiyang Zhao, Zhuowei Tian, Yanan Wang, Meng Xiao, Zhong Du
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