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<p>Neuromyelitis optica spectrum disorder (NMOSD) is a rare neurological autoimmune disease caused by autoantibodies targeting the astrocytic water channel aquaporin-4 (AQP4). Binding to AQP4 initiates the activation of innate immune components, especially the complement system. Both in-vivo and in-vitro models have been developed to study the molecular pathophysiology of NMOSD. Our study aimed to characterize the molecular response of four human cell lines (AQP4-ECFP expressing U-87MG glioblastoma cells, U-87MG expressing only ECFP, HEK293 cells expressing AQP4-EmGFP, and human primary astrocytes) to a treatment with AQP4 antibody E5415A and human complement. Complement-dependent cytotoxicity was induced by this treatment in AQP4-expressing cells by the terminal complement pathway. Transcriptomic profiles of the in-vitro U-87MG-AQP4-ECFP model and an in-vivo rat model shared a proinflammatory shift towards NF-κB and interleukin-6 pathways. These findings were confirmed at both the mRNA and protein levels, and treatment with serum samples from AQP4 antibody seropositive NMOSD patients resulted in a similar response. Additionally, NF-κB upregulation was shown by immunohistochemistry in medulla oblongata lesions of NMOSD patients. In conclusion, interleukin-6 and NF-κB pathways play a key role in inflammation caused by the activation of the terminal complement pathway in a human cellular model of NMOSD using U-87MG-AQP4-ECFP cells.</p>

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Inflammatory transcriptomic signatures in a human cellular NMOSD model reveal upregulation of NF-κB and IL6 pathways

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月8日

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  • Sarah Brandl,
  • Qian Yu,
  • Judith Hagenbuchner,
  • Verena Endmayr,
  • Romana Höftberger,
  • Monika Bradl,
  • Markus Reindl

摘要

Neuromyelitis optica spectrum disorder (NMOSD) is a rare neurological autoimmune disease caused by autoantibodies targeting the astrocytic water channel aquaporin-4 (AQP4). Binding to AQP4 initiates the activation of innate immune components, especially the complement system. Both in-vivo and in-vitro models have been developed to study the molecular pathophysiology of NMOSD. Our study aimed to characterize the molecular response of four human cell lines (AQP4-ECFP expressing U-87MG glioblastoma cells, U-87MG expressing only ECFP, HEK293 cells expressing AQP4-EmGFP, and human primary astrocytes) to a treatment with AQP4 antibody E5415A and human complement. Complement-dependent cytotoxicity was induced by this treatment in AQP4-expressing cells by the terminal complement pathway. Transcriptomic profiles of the in-vitro U-87MG-AQP4-ECFP model and an in-vivo rat model shared a proinflammatory shift towards NF-κB and interleukin-6 pathways. These findings were confirmed at both the mRNA and protein levels, and treatment with serum samples from AQP4 antibody seropositive NMOSD patients resulted in a similar response. Additionally, NF-κB upregulation was shown by immunohistochemistry in medulla oblongata lesions of NMOSD patients. In conclusion, interleukin-6 and NF-κB pathways play a key role in inflammation caused by the activation of the terminal complement pathway in a human cellular model of NMOSD using U-87MG-AQP4-ECFP cells.