Skip to main content

Advertisement

SpringerLink
Log in

GM-CSF Promotes the Development of Dysfunctional Vascular Networks in Moyamoya Disease

  • Original Article
  • Published:
Neuroscience Bulletin Aims and scope Submit manuscript

Abstract

Moyamoya disease (MMD) is a chronic occlusive cerebrovascular disease with the development of a network of abnormal vessels. Immune inflammation is associated with the occurrence and development of MMD. However, the mechanisms underlying the formation of the abnormal vascular network remain unclear. Twenty-eight patients with MMD, 26 ischemic stroke patients, and 26 unrelated healthy volunteers were enrolled in this study The data showed that the levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) were higher in MMD patients than in healthy controls (P <0.01), and GM-CSF was mainly from Th1 and Th17 cells in MMD. We found that increased GM-CSF drove monocytes to secrete a series of cytokines associated with angiogenesis, inflammation, and chemotaxis. In summary, our findings demonstrate for the first time the important involvement of GM-CSF in MMD and that GM-CSF is an important factor in the formation of abnormal vascular networks in MMD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Kuroda S, Houkin K. Moyamoya disease: Current concepts and future perspectives. Lancet Neurol 2008, 7: 1056–1066.

    Article  PubMed  Google Scholar 

  2. Ihara M, Yamamoto Y, Hattori Y, Liu W, Kobayashi H, Ishiyama H. Moyamoya disease: Diagnosis and interventions. Lancet Neurol 2022, 21: 747–758.

    Article  CAS  PubMed  Google Scholar 

  3. Sun Y, Zhou G, Feng J, Chen L, Liu G, Wang J, et al. Incidence and prevalence of moyamoya disease in urban China: A nationwide retrospective cohort study. Stroke Vasc Neurol 2021, 6: 615–623.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Cui TA, Ding ZK. Study on reversible anticholinesterase agents: Synthesis of derivatives of 1, 3, 2-dioxaphosphorinane 2-oxide. Yao Xue Xue Bao 1987, 22: 827–832.

    CAS  PubMed  Google Scholar 

  5. Kundishora AJ, Peters ST, Pinard A, Duran D, Panchagnula S, Barak T, et al. DIAPH1 variants in non-east Asian patients with sporadic moyamoya disease. JAMA Neurol 2021, 78: 993–1003.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Liu W, Morito D, Takashima S, Mineharu Y, Kobayashi H, Hitomi T, et al. Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development. PLoS One 2011, 6: e22542.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Okazaki S, Morimoto T, Kamatani Y, Kamimura T, Kobayashi H, Harada K, et al. Moyamoya disease susceptibility variant RNF213 p.R4810K increases the risk of ischemic stroke attributable to large-artery atherosclerosis. Circulation 2019, 139: 295–298.

    Article  CAS  PubMed  Google Scholar 

  8. Masuda J, Ogata J, Yutani C. Smooth muscle cell proliferation and localization of macrophages and T cells in the occlusive intracranial major arteries in moyamoya disease. Stroke 1993, 24: 1960–1967.

    Article  CAS  PubMed  Google Scholar 

  9. Peng X, Zhang Z, Ye D, Xing P, Zou Z, Lei H, et al. Gene dysregulation in peripheral blood of moyamoya disease and comparison with other vascular disorders. PLoS One 2019, 14: e0221811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Jin F, Duan C. Identification of immune-infiltrated hub genes as potential biomarkers of Moyamoya disease by bioinformatics analysis. Orphanet J Rare Dis 2022, 17: 80.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Weng L, Cao X, Han L, Zhao H, Qiu S, Yan Y, et al. Association of increased Treg and Th17 with pathogenesis of moyamoya disease. Sci Rep 2017, 7: 3071.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Zhang X, He B, Li H, Wang Y, Zhou Y, Wang W, et al. SOCS3 attenuates GM-CSF/IFN-γ-mediated inflammation during spontaneous spinal cord regeneration. Neurosci Bull 2020, 36: 778–792.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lehtonen A, Matikainen S, Miettinen M, Julkunen I. Granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced STAT5 activation and target-gene expression during human monocyte/macrophage differentiation. J Leukoc Biol 2002, 71: 511–519.

    Article  CAS  PubMed  Google Scholar 

  14. Hansen G, Hercus TR, McClure BJ, Stomski FC, Dottore M, Powell J, et al. The structure of the GM-CSF receptor complex reveals a distinct mode of cytokine receptor activation. Cell 2008, 134: 496–507.

    Article  CAS  PubMed  Google Scholar 

  15. Shiomi A, Usui T. Pivotal roles of GM-CSF in autoimmunity and inflammation. Mediators Inflamm 2015, 2015: 568543.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Wicks IP, Roberts AW. Targeting GM-CSF in inflammatory diseases. Nat Rev Rheumatol 2016, 12: 37–48.

    Article  CAS  PubMed  Google Scholar 

  17. Lotfi N, Thome R, Rezaei N, Zhang GX, Rezaei A, Rostami A, et al. Roles of GM-CSF in the pathogenesis of autoimmune diseases: An update. Front Immunol 2019, 10: 1265.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wroblewski M, Bauer R, Cubas Córdova M, Udonta F, Ben-Batalla I, Legler K, et al. Mast cells decrease efficacy of anti-angiogenic therapy by secreting matrix-degrading granzyme B. Nat Commun 2017, 8: 269.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhu SN, Chen M, Jongstra-Bilen J, Cybulsky MI. GM-CSF regulates intimal cell proliferation in nascent atherosclerotic lesions. J Exp Med 2009, 206: 2141–2149.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Fujimura M, Tominaga T. Diagnosis of moyamoya disease: International standard and regional differences. Neurol Med Chir (Tokyo) 2015, 55: 189–193.

    Article  PubMed  Google Scholar 

  21. Kanat A, Tsianaka E, Gasenzer ER, Drosos E. Some interesting points of competition of X-ray using during the greco-ottoman war in 1897 and development of neurosurgical radiology: A reminiscence. Turk Neurosurg 2022, 32: 877–881.

    PubMed  Google Scholar 

  22. Jauch EC, Saver JL, Adams HP Jr, Bruno A, Buddy Connors JJ, Demaerschalk BM, et al. Guidelines for the early management of patients with acute ischemic stroke: A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013, 44: 870–947.

    Article  PubMed  Google Scholar 

  23. Komuczki J, Tuzlak S, Friebel E, Hartwig T, Spath S, Rosenstiel P, et al. Fate-mapping of GM-CSF expression identifies a discrete subset of inflammation-driving T helper cells regulated by cytokines IL-23 and IL-1β. Immunity 2019, 50: 1289-1304.e6.

    Article  CAS  PubMed  Google Scholar 

  24. Achuthan AA, Lee KMC, Hamilton JA. Targeting GM-CSF in inflammatory and autoimmune disorders. Semin Immunol 2021, 54: 101523.

    Article  CAS  PubMed  Google Scholar 

  25. Ingelfinger F, de Feo D, Becher B. GM-CSF: Master regulator of the T cell-phagocyte interface during inflammation. Semin Immunol 2021, 54: 101518.

    Article  CAS  PubMed  Google Scholar 

  26. Croxford AL, Lanzinger M, Hartmann FJ, Schreiner B, Mair F, Pelczar P, et al. The cytokine GM-CSF drives the inflammatory signature of CCR2+ monocytes and licenses autoimmunity. Immunity 2015, 43: 502–514.

    Article  CAS  PubMed  Google Scholar 

  27. Koh MY, Toh KZ, Ho JS, Yeo LL, Ho AF, Sia CH, et al. Intravenous thrombolysis and endovascular thrombectomy for acute ischaemic stroke in patients with Moyamoya disease - a systematic review and meta-summary of case reports. J Thromb Thrombolysis 2022, 54: 339–349.

    Article  PubMed  Google Scholar 

  28. Lin R, Xie Z, Zhang J, Xu H, Su H, Tan X, et al. Clinical and immunopathological features of Moyamoya disease. PLoS One 2012, 7: e36386.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Restorick SM, Durant L, Kalra S, Hassan-Smith G, Rathbone E, Douglas MR, et al. CCR6+ Th cells in the cerebrospinal fluid of persons with multiple sclerosis are dominated by pathogenic non-classic Th1 cells and GM-CSF-only-secreting Th cells. Brain Behav Immun 2017, 64: 71–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kang HS, Kim JH, Phi JH, Kim YY, Kim JE, Wang KC, et al. Plasma matrix metalloproteinases, cytokines and angiogenic factors in moyamoya disease. J Neurol Neurosurg Psychiatry 2010, 81: 673–678.

    Article  PubMed  Google Scholar 

  31. Sakamoto S, Kiura Y, Yamasaki F, Shibukawa M, Ohba S, Shrestha P, et al. Expression of vascular endothelial growth factor in dura mater of patients with moyamoya disease. Neurosurg Rev 2008, 31: 77–81;discussion81.

  32. Takahashi A, Sawamura Y, Houkin K, Kamiyama H, Abe H. The cerebrospinal fluid in patients with moyamoya disease (spontaneous occlusion of the circle of Willis) contains high level of basic fibroblast growth factor. Neurosci Lett 1993, 160: 214–216.

    Article  CAS  PubMed  Google Scholar 

  33. Yoshimoto T, Houkin K, Takahashi A, Abe H. Angiogenic factors in moyamoya disease. Stroke 1996, 27: 2160–2165.

    Article  CAS  PubMed  Google Scholar 

  34. Eubank TD, Roberts R, Galloway M, Wang Y, Cohn DE, Marsh CB. GM-CSF induces expression of soluble VEGF receptor-1 from human monocytes and inhibits angiogenesis in mice. Immunity 2004, 21: 831–842.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Eubank TD, Roda JM, Liu H, O’Neil T, Marsh CB. Opposing roles for HIF-1α and HIF-2α in the regulation of angiogenesis by mononuclear phagocytes. Blood 2011, 117: 323–332.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Roda JM, Sumner LA, Evans R, Phillips GS, Marsh CB, Eubank TD. Hypoxia-inducible factor-2α regulates GM-CSF-derived soluble vascular endothelial growth factor receptor 1 production from macrophages and inhibits tumor growth and angiogenesis. J Immunol 2011, 187: 1970–1976.

    Article  CAS  PubMed  Google Scholar 

  37. Zhao J, Chen L, Shu B, Tang J, Zhang L, Xie J, et al. Granulocyte/macrophage colony-stimulating factor influences angiogenesis by regulating the coordinated expression of VEGF and the Ang/Tie system. PLoS One 2014, 9: e92691.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Cianfarani F, Tommasi R, Failla CM, Viviano MT, Annessi G, Papi M, et al. Granulocyte/macrophage colony-stimulating factor treatment of human chronic ulcers promotes angiogenesis associated with de novo vascular endothelial growth factor transcription in the ulcer bed. Br J Dermatol 2006, 154: 34–41.

    Article  CAS  PubMed  Google Scholar 

  39. Grote K, Schuett H, Salguero G, Grothusen C, Jagielska J, Drexler H, et al. Toll-like receptor 2/6 stimulation promotes angiogenesis via GM-CSF as a potential strategy for immune defense and tissue regeneration. Blood 2010, 115: 2543–2552.

    Article  CAS  PubMed  Google Scholar 

  40. Valdembri D, Serini G, Vacca A, Ribatti D, Bussolino F. In vivo activation of JAK2/STAT-3 pathway during angiogenesis induced by GM-CSF. FASEB J 2002, 16: 225–227.

    Article  CAS  PubMed  Google Scholar 

  41. Miao W, Zhao PL, Zhang YS, Liu HY, Chang Y, Ma J, et al. Epidemiological and clinical features of Moyamoya disease in Nanjing. China. Clin Neurol Neurosurg 2010, 112: 199–203.

    Article  PubMed  Google Scholar 

  42. Wang W, Jiang B, Sun H, Ru X, Sun D, Wang L, et al. Prevalence, incidence, and mortality of stroke in China: Results from a nationwide population-based survey of 480 687 adults. Circulation 2017, 135: 759–771.

    Article  PubMed  Google Scholar 

  43. Yao Z, Huang L, Chen Y, Qi R, Xu B, Zhang Q, et al. Clinical characteristics and outcomes of acute ischemic stroke in patients with COVID-19: A systematic review and meta-analysis of global data. Adv Neuro 2022, 1: 1–16.

    Article  Google Scholar 

Download references

Acknowledgements

We gratefully thank all the patients and healthy volunteers for participating in our study. This work was supported by the National Natural Science Foundation of China (82271334, 82130036, 81920108017, and 82171310), the National Science and Technology Innovation 2030 -- Major Program of "Brain Science and Brain-Like Research" (2022ZD0211800), Jiangsu Provincial ‘333’ High-level Talent Training Project Funding, the Key Research and Development Program of Jiangsu Province of China (BE2020620), and Jiangsu Province Key Medical Discipline (ZDXK202216).

Author information

Author notes

  1. Huiqin Li, Xiang Cao, and Xinya Gu contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology and Neurosurgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China

    Huiqin Li, Xiang Cao, Lili Huang, Chenglu Mao, Shengnan Xia, Haiyan Yang, Xinyu Bao, Yongbo Yang & Yun Xu

  2. Department of Neurology and Neurosurgery, Nanjing Drum Tower Hospital, State Key Laboratory of Pharmaceutical Biotechnology and Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, 210008, China

    Xiang Cao & Yun Xu

  3. Department of Neurology and Neurosurgery, Nanjing Drum Tower Hospital Clinical College of Xuzhou Medical University, Nanjing, 210008, China

    Xinya Gu & Yun Xu

  4. Department of Neurology and Neurosurgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, 210008, China

    Xiang Cao, Mengqi Dong & Yun Xu

  5. Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, 210008, China

    Xiang Cao & Yun Xu

  6. Jiangsu Provincial Key Discipline of Neurology, Nanjing, 210008, China

    Xiang Cao & Yun Xu

  7. Nanjing Neurology Medical Center, Nanjing, 210008, China

    Xiang Cao & Yun Xu

Authors
  1. Huiqin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiang Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xinya Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mengqi Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lili Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chenglu Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shengnan Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Haiyan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xinyu Bao
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yongbo Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yun Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yongbo Yang or Yun Xu.

Ethics declarations

Conflict of interest

All authors claim that there are no conflicts of interest.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 424 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, H., Cao, X., Gu, X. et al. GM-CSF Promotes the Development of Dysfunctional Vascular Networks in Moyamoya Disease. Neurosci. Bull. 40, 451–465 (2024). https://doi.org/10.1007/s12264-023-01158-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12264-023-01158-y

Keywords

Search

Navigation