Trends in Immunotherapy

Article

Targeting Notch1 for Neuroinflammatory Immunotherapy: Insights from a Neuronal Apoptosis Model

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https://doi.org/10.54963/ti.v9i2.1063
Jiang, S., & Wei, X. (2025). Targeting Notch1 for Neuroinflammatory Immunotherapy: Insights from a Neuronal Apoptosis Model . Trends in Immunotherapy, 9(2), 27–44. https://doi.org/10.54963/ti.v9i2.1063
Volume 9 Issue 2 (2025): (in progress)
Copyright (c) 2025 Shuyuan Jiang, Xie Wei
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Authors

  • Shuyuan Jiang

    Department of Public Health, International College, Krirk University, Bang Khen, Bangkok 10220, Thailand
  • Xie Wei

    Department of Public Health, International College, Krirk University, Bang Khen, Bangkok 10220, Thailand

The Notch1 signaling pathway is pivotal in neuroimmunomodulation and inflammation, and it significantly contributes to the development and pathogenesis of the nervous system. Consequently, targeting Notch signaling may offer a promising therapeutic approach for neurological disorders. In this investigation, we elucidated the crucial role of Notch1 signaling in neuronal apoptosis, immune regulation, and inflammatory signaling by knocking down the Notch1 gene in mouse hippocampal HT22 cells. Suppression of Notch1 resulted in a marked reduction in the expression of its downstream effector molecule Hes1, accompanied by a significant rise in apoptosis, increased levels of apoptosis-related proteins, and diminished cell viability. RNA sequencing analyses further revealed that differential expression was closely linked to apoptosis, immune-regulatory pathways, and inflammatory signaling. Apoptosis serves as a critical mechanism for eliminating abnormal cells and can impact immune response balance by modulating immune cell activation and function. Notch1 signaling can indirectly affect the neuroimmune microenvironment by regulating neuronal apoptosis. Thus, targeting the Notch1 signaling pathway not only safeguards neuronal function by inhibiting apoptosis but also modulates immune cell activation and inflammatory responses, offering a novel strategy for the immunotherapy of neurodegenerative and cerebrovascular diseases. Comprehending this mechanism provides a crucial foundation for exploring Notch1 immunotherapy for these conditions. By precisely modulating Notch1 signaling, it is anticipated that future therapies can achieve the dual benefits of neuroprotection and immunomodulation, paving the way for innovative treatments for related diseases.

Keywords:

Notch1; Neuroinϐlammatory; Immunotherapy; Apoptosis; Neurodegenerative Diseases

Highlights

Received: 5 March 2025; Revised: 8 March 2025; Accepted: 9 March 2025; Published: 7 May 2025

References

  1. Bigas, A.; Espinosa, L. Hematopoietic stem cells: to be or Notch to be. Blood 2012, 119, 3226-3235. DOI: https://doi.org/10.1182/blood-2011-10-355826
  2. Koch, U.; Lehal, R.; Radtke, F. Stem cells living with a Notch. Development 2013, 140, 689-704. DOI: https://doi.org/10.1242/dev.080614
  3. Klinakis, A.; Lobry, C.; Abdel-Wahab, O.; et al. A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia. Nature 2011, 473, 230-233. DOI: https://doi.org/10.1038/nature09999
  4. Wang, M.; Yu, F.; Zhang, Y.; et al. Novel insights into Notch signaling in tumor immunity: potential targets for cancer immunotherapy. Front. Immunol.2024, 15, 1352484. DOI: https://doi.org/10.3389/fimmu.2024.1352484
  5. Alberi, L.; Liu, S.; Wang, Y.; et al. Activity-induced Notch signaling in neurons requires Arc/Arg3.1 and is essential for synaptic plasticity in hippocampal networks. Neuron 2011, 69, 437-444. DOI: https://doi.org/10.1016/j.neuron.2011.01.004
  6. Ables, J.L.; Breunig, J.J.; Eisch, A.J.; et al. Not(ch) just development: Notch signalling in the adult brain. Nat. Rev. Neurosci. 2011, 12, 269-283. DOI: https://doi.org/10.1038/nrn3024
  7. Wang, Y.; Chan, S.L.; Miele, L.; et al. Involvement of Notch signaling in hippocampal synaptic plasticity. Proc. Natl. Acad. Sci. USA 2004, 101, 9458-9462. DOI: https://doi.org/10.1073/pnas.0308126101
  8. Ding, X.F.; Gao, X.; Ding, X.C.; et al. Postnatal dysregulation of Notch signal disrupts dendrite development of adult-born neurons in the hippocampus and contributes to memory impairment. Sci. Rep. 2016, 6, 25780. DOI: https://doi.org/10.1038/srep25780
  9. Louvi, A.; Artavanis-Tsakonas, S. Notch and disease: a growing field. Semin. Cell Dev. Biol. 2012, 23, 473-480. DOI: https://doi.org/10.1016/j.semcdb.2012.02.005
  10. Cohen, J.; Mathew, A.; Dourvetakis, K.D.; et al. Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders. Cells 2024, 13. DOI: https://doi.org/10.3390/cells13060511
  11. Alsbrook, D.L.; Di Napoli, M.; Bhatia, K.; et al. Neuroinflammation in Acute Ischemic and Hemorrhagic Stroke. Curr. Neurol. Neurosci. Rep. 2023, 23, 407-431. DOI: https://doi.org/10.1007/s11910-023-01282-2
  12. Tater, P.; Pandey, S. Post-stroke Movement Disorders: Clinical Spectrum, Pathogenesis, and Management. Neurol. India 2021, 69, 272-283. DOI: https://doi.org/10.4103/0028-3886.314574
  13. Pajares, M.; A, I.R.; Manda, G.; et al. Inflammation in Parkinson's Disease: Mechanisms and Therapeutic Implications. Cells 2020, 9. DOI: https://doi.org/10.3390/cells9071687
  14. Androutsellis-Theotokis, A.; Leker, R.R.; Soldner, F.; et al. Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 2006, 442, 823-826. DOI: https://doi.org/10.1038/nature04940
  15. Sun, F.; Mao, X.; Xie, L.; et al. Notch1 signaling modulates neuronal progenitor activity in the subventricular zone in response to aging and focal ischemia. Aging Cell 2013, 12, 978-987. DOI: https://doi.org/10.1111/acel.12134
  16. Chen, M.; Lu, T.J.; Chen, X.J.; et al. Differential roles of NMDA receptor subtypes in ischemic neuronal cell death and ischemic tolerance. Stroke 2008, 39, 3042-3048. DOI: https://doi.org/10.1161/strokeaha.108.521898
  17. Kawai, T.; Takagi, N.; Nakahara, M.; et al. Changes in the expression of Hes5 and Mash1 mRNA in the adult rat dentate gyrus after transient forebrain ischemia. Neurosci. Lett. 2005, 380, 17-20. DOI: https://doi.org/10.1016/j.neulet.2005.01.005
  18. Wang, L.; Chopp, M.; Zhang, R.L.; et al. The Notch pathway mediates expansion of a progenitor pool and neuronal differentiation in adult neural progenitor cells after stroke. Neuroscience 2009, 158, 1356-1363. DOI: https://doi.org/10.1016/j.neuroscience.2008.10.064
  19. Li, Z.; Wang, J.; Zhao, C.; et al. Acute Blockage of Notch Signaling by DAPT Induces Neuroprotection and Neurogenesis in the Neonatal Rat Brain After Stroke. Transl. Stroke Res. 2016, 7, 132-140. DOI: https://doi.org/10.1007/s12975-015-0441-7
  20. Arumugam, T.V.; Baik, S.H.; Balaganapathy, P.; et al. Notch signaling and neuronal death in stroke. Prog. Neurobiol. 2018, 165-167, 103-116. DOI: https://doi.org/10.1016/j.pneurobio.2018.03.002
  21. Yao, Y.Y.; Li, R.; Guo, Y.J.; et al. Gastrodin Attenuates Lipopolysaccharide-Induced Inflammatory Response and Migration via the Notch-1 Signaling Pathway in Activated Microglia. Neuromol. Med. 2022, 24, 139-154. DOI: https://doi.org/10.1007/s12017-021-08671-1
  22. Zhang, Y.H.; Wang, T.; Li, Y.F.; et al. Roles of the Notch signaling pathway and microglia in autism. Behav. Brain Res. 2023, 437, 114131. DOI: https://doi.org/10.1016/j.bbr.2022.114131
  23. Wu, F.; Zuo, H.J.; Ren, X.Q.; et al. Gastrodin Regulates the Notch-1 Signal Pathway via Renin-Angiotensin System in Activated Microglia. Neuromol. Med. 2023, 25, 40-52. DOI: https://doi.org/10.1007/s12017-022-08714-1
  24. Bassil, R.; Orent, W.; Elyaman, W. Notch signaling and T-helper cells in EAE/MS. Clin. Dev. Immunol. 2013, 2013, 570731. DOI: https://doi.org/10.1155/2013/570731
  25. Bassil, R.; Zhu, B.; Lahoud, Y.; et al. Notch ligand delta-like 4 blockade alleviates experimental autoimmune encephalomyelitis by promoting regulatory T cell development. J. Immunol. 2011, 187, 2322-2328. DOI: https://doi.org/10.4049/jimmunol.1100725
  26. Liang, J.; Han, S.; Ye, C.; et al. Minocycline Attenuates Sevoflurane-Induced Postoperative Cognitive Dysfunction in Aged Mice by Suppressing Hippocampal Apoptosis and the Notch Signaling Pathway-Mediated Neuroinflammation. Brain Sci. 2023, 13. DOI: https://doi.org/10.3390/brainsci13030512
  27. Yu, B.; Song, B. Notch 1 signalling inhibits cardiomyocyte apoptosis in ischaemic postconditioning. Heart Lung Circul. 2014, 23, 152-158. DOI: https://doi.org/10.1016/j.hlc.2013.07.004
  28. Nair, P.; Somasundaram, K.; Krishna, S. Activated Notch1 inhibits p53-induced apoptosis and sustains transformation by human papillomavirus type 16 E6 and E7 oncogenes through a PI3K-PKB/Akt-dependent pathway. J. Virol. 2003, 77, 7106-7112. DOI: https://doi.org/10.1128/jvi.77.12.7106-7112.2003
  29. Lan, L.; Wang, Y.; Pan, Z.; et al. Rhamnetin induces apoptosis in human breast cancer cells via the miR-34a/Notch-1 signaling pathway. Oncol. Lett. 2019, 17, 676-682. DOI: https://doi.org/10.3892/ol.2018.9575
  30. Xiang, Z.; Miao, Q.; Zhang, J.; et al. AB4 inhibits Notch signaling and promotes cancer cell apoptosis in liver cancer. Oncol. Rep. 2021, 45. DOI: https://doi.org/10.3892/or.2021.8063
  31. Zhao, Z.; Lu, R.; Zhang, B.; et al. Differentiation of HT22 neurons induces expression of NMDA receptor that mediates homocysteine cytotoxicity. Neurol. Res. 2012, 34, 38-43. DOI: https://doi.org/10.1179/1743132811y.0000000057
  32. Chang, Z.; Xu, W.; Jiang, S.; et al. Effects of 5-Aza on neurogenesis contribute to learning and memory in the mouse hippocampus. Biomed. Pharmacother. = Biomed. pharmacother. 2022, 154, 113623. DOI: https://doi.org/10.1016/j.biopha.2022.113623
  33. Tian, X.L.; Jiang, S.Y.; Zhang, X.L.; et al. Potassium bisperoxo (1,10-phenanthroline) oxovanadate suppresses proliferation of hippocampal neuronal cell lines by increasing DNA methyltransferases. Neural Regen. Res. 2019, 14, 826-833. DOI: https://doi.org/10.4103/1673-5374.249230
  34. Liu, N.; Zhang, X.L.; Jiang, S.Y.; et al. Neuroprotective mechanisms of DNA methyltransferase in a mouse hippocampal neuronal cell line after hypoxic preconditioning. Neural Regen. Res. 2020, 15, 2362-2368. DOI: https://doi.org/10.4103/1673-5374.285003
  35. Lu, F.; Zhu, J.; Guo, S.; et al. Upregulation of cholesterol 24-hydroxylase following hypoxia-ischemia in neonatal mouse brain. Pediatr. Res. 2018, 83, 1218-1227. DOI: https://doi.org/10.1038/pr.2018.49
  36. Eskandari, E.; Eaves, C.J. Paradoxical roles of caspase-3 in regulating cell survival, proliferation, and tumorigenesis. J. Cell Biol. 2022, 221. DOI: https://doi.org/10.1083/jcb.202201159
  37. Zhu, L.; Chen, Y.; Ding, W.; et al. Caspase-3/Treg and PI3K/AKT/mTOR pathway is involved in Liver Ischemia Reperfusion Injury (IRI) protection by everolimus. Transpl. Immunol. 2022, 71, 101541. DOI: https://doi.org/10.1016/j.trim.2022.101541
  38. Zapata-Lopera, Y.M.; Trejo-Tapia, G.; Cano-Europa, E.; et al. Neuroprotective effect of Bouvardia ternifolia (Cav.) Schltdl via inhibition of TLR4/NF-κB, caspase-3/Bax/Bcl-2 pathways in ischemia/reperfusion injury in rats. Front. Pharmacol. 2024, 15, 1471542. DOI: https://doi.org/10.3389/fphar.2024.1471542
  39. Fan, W.; Dai, Y.; Xu, H.; et al. Caspase-3 modulates regenerative response after stroke. Stem Cells 2014, 32, 473-486. DOI: https://doi.org/10.1002/stem.1503
  40. Mora, P.; Chapouly, C. Astrogliosis in multiple sclerosis and neuro-inflammation: what role for the notch pathway? Front. Immunol. 2023, 14, 1254586. DOI: https://doi.org/10.3389/fimmu.2023.1254586
  41. Mochizuki, K.; He, S.; Zhang, Y. Notch and inflammatory T-cell response: new developments and challenges. Immunotherapy 2011, 3, 1353-1366. DOI: https://doi.org/10.2217/imt.11.126
  42. Zhang, Y.; Wang, T.; Wu, S.; et al. Notch signaling pathway: a new target for neuropathic pain therapy. J. Headache Pain 2023, 24, 87. DOI: https://doi.org/10.1186/s10194-023-01616-y
  43. Yashiro-Ohtani, Y.; Ohtani, T.; Pear, W.S. Notch regulation of early thymocyte development. Semin. Immunol. 2010, 22, 261-269. DOI: https://doi.org/10.1016/j.smim.2010.04.015
  44. Tanigaki, K.; Honjo, T. Regulation of lymphocyte development by Notch signaling. Nature Immunol. 2007, 8, 451-456. DOI: https://doi.org/10.1038/ni1453
  45. Eagar, T.N.; Tang, Q.; Wolfe, M.; et al. Notch 1 signaling regulates peripheral T cell activation. Immunity 2004, 20, 407-415. DOI: https://doi.org/10.1016/s1074-7613(04)00081-0
  46. Ostroukhova, M.; Qi, Z.; Oriss, T.B.; et al. Treg-mediated immunosuppression involves activation of the Notch-HES1 axis by membrane-bound TGF-beta. J. Clin. Investig. 2006, 116, 996-1004. DOI: https://doi.org/10.1172/jci26490
  47. Li, X.; Yan, X.; Wang, Y.; et al. The Notch signaling pathway: a potential target for cancer immunotherapy. J. Hematol. Oncol. 2023, 16, 45. DOI: https://doi.org/10.1186/s13045-023-01439-z
  48. Blanquie, O.; Kilb, W.; Sinning, A.; et al. Homeostatic interplay between electrical activity and neuronal apoptosis in the developing neocortex. Neuroscience 2017, 358, 190-200. DOI: https://doi.org/10.1016/j.neuroscience.2017.06.030
  49. Bredesen, D.E. Genetic control of neural cell apoptosis. Perspect. Dev. Neurobiol. 1996, 3, 101-109.
  50. Passeri, E.; Elkhoury, K. Alzheimer's Disease: Treatment Strategies and Their Limitations. Brain Sci. 2022, 23. DOI: https://doi.org/10.3390/ijms232213954
  51. Dhapola, R.; Hota, S.S.; Sarma, P.; et al. Recent advances in molecular pathways and therapeutic implications targeting neuroinflammation for Alzheimer's disease. Inflammopharmacology 2021, 29, 1669-1681. DOI: https://doi.org/10.1007/s10787-021-00889-6
  52. Xiao, P.; Zhang, X.; Li, Y.; et al. miR-9 inhibition of neuronal apoptosis and expression levels of apoptosis genes Bcl-2 and Bax in depression model rats through Notch pathway. Exp. Ther. Med. 2020, 19, 551-556. DOI: https://doi.org/10.3892/etm.2019.8228
  53. Chen, Z.; Liu, J.; Chen, Q.; et al. Down-regulation of UBA6 exacerbates brain injury by inhibiting the activation of Notch signaling pathway to promote cerebral cell apoptosis in rat acute cerebral infarction model. Mol. Cell. Probes 2020, 53, 101612. DOI: https://doi.org/10.1016/j.mcp.2020.101612
  54. Patterson, L.L.; Byerly, C.D.; Solomon, R.; et al. Ehrlichia Notch signaling induction promotes XIAP stability and inhibits apoptosis. Infect. Immunity 2023, 91, e0000223. DOI: https://doi.org/10.1128/iai.00002-23
  55. Wu, H.; Chen, Q.Y.; Wang, W.Z.; et al. Compound sophorae decoction enhances intestinal barrier function of dextran sodium sulfate induced colitis via regulating notch signaling pathway in mice. Biomed. Pharmacother. = Biomed. Pharmacother. 2021, 133, 110937. DOI: https://doi.org/10.1016/j.biopha.2020.110937
  56. Zhang, K.; Zhao, T.; Huang, X.; Notch1 mediates postnatal neurogenesis in hippocampus enhanced by intermittent hypoxia. Neurobiol. Dis. 2014, 64, 66-78. DOI: https://doi.org/10.1016/j.nbd.2013.12.010
  57. Ables, J.L.; Decarolis, N.A.; Johnson, M.A.; et al. Notch1 is required for maintenance of the reservoir of adult hippocampal stem cells. J. Neurosci. off. J. Soc. Neurosci. 2010, 30, 10484-10492. DOI: https://doi.org/10.1523/jneurosci.4721-09.2010
  58. Goetzl, E.J.; Schwartz, J.B.; Abner, E.L.; et al. High complement levels in astrocyte-derived exosomes of Alzheimer disease. Ann. Neurol. 2018, 83, 544-552. DOI: https://doi.org/10.1002/ana.25172
  59. Cao, Q.; Karthikeyan, A.; Dheen, S.T.; et al. Production of proinflammatory mediators in activated microglia is synergistically regulated by Notch-1, glycogen synthase kinase (GSK-3β) and NF-κB/p65 signalling. PLoS ONE 2017, 12, e0186764. DOI: https://doi.org/10.1371/journal.pone.0186764
  60. Deng, X.L.; Feng, L.; Wang, Z.X.; et al. The Runx1/Notch1 Signaling Pathway Participates in M1/M2 Microglia Polarization in a Mouse Model of Temporal Lobe Epilepsy and in BV-2 Cells. Neurochem. Res. 2020, 45, 2204-2216. DOI: https://doi.org/10.1007/s11064-020-03082-3
  61. Zheng, J.; Zhang, J.; Han, J.; et al. The effect of salidroside in promoting endogenous neural regeneration after cerebral ischemia/reperfusion involves notch signaling pathway and neurotrophic factors. BMC Complement. Med. Ther. 2024, 24, 293. DOI: https://doi.org/10.1186/s12906-024-04597-w
  62. Li, X.; Huang, H.; Li, Y.; et al. Gualou Guizhi Granule inhibits microglia-mediated neuroinflammation to protect against neuronal apoptosis in vitro and in vivo. Front. Immunol. 2024, 15, 1527986. DOI: https://doi.org/10.3389/fimmu.2024.1527986
  63. Yang, H.; Gao, X.; Xiao, W.; et al. Minocycline Alleviates White Matter Injury following Intracerebral Hemorrhage by Regulating CD4+ T Cell Differentiation via Notch1 Signaling Pathway. Oxid. Med. Cell. Longev. 2022, 2022, 3435267. DOI: https://doi.org/10.1155/2022/3435267
  64. Radtke, F.; Wilson, A.; Mancini, S.J.; et al. Notch regulation of lymphocyte development and function. Nat. Immunol. 2004, 5, 247-253. DOI: https://doi.org/10.1038/ni1045
  65. Amsen, D.; Blander, J.M.; Lee, G.R.; et al. Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells. Cell 2004, 117, 515-526. DOI: https://doi.org/10.1016/s0092-8674(04)00451-9