Chen Siqi, Zhang Yurong, Liu Kaiqun, Xiao Zhiqiang, Liu Xiaoning, Xu Ziyan, Qiu Wei, Xu Ying, Tang Changyong, Yang Hui
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology Visual Science, Guangzhou, Guangdong Province, China.
Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China.
Eur J Neurosci. 2025 Apr;61(8):e70103. doi: 10.1111/ejn.70103.
Accumulating evidence suggests that the complement C3/C3a receptor (C3aR) pathway plays a pivotal role in the pathogenesis of neurodegenerative and autoimmune disorders, particularly neuromyelitis optica spectrum disorders (NMOSDs). Despite this, the specific pathogenic effect and mechanism of C3/C3aR pathway in NMOSD remains elusive. In this study, we demonstrated for the first time that the expression of C3aR and its upstream ligand C3 is significantly upregulated in the optic nerve of a rat model of NMOSD-related optic neuritis (NMOSD-ON). Our findings reveal that this upregulation leads to blood-brain barrier (BBB) disruption, demyelination and neuronal damage. Through the use of a novel C3aR inhibitor, JR14a, we demonstrate its effectiveness in reducing C3aR expression and mitigating pathological damage in the optic nerve. Furthermore, our transcriptome sequencing analysis of NMOSD optic nerve tissues reveals extensive enrichment of inflammation- and immune response-related pathways, with particular emphasis on the complement and coagulation cascades pathway. This study not only elucidated the crucial role of the C3-C3aR pathway in NMOSD-ON pathogenesis but also provided a new promising therapeutic target for NMOSD through C3aR pathway inhibition.
越来越多的证据表明，补体C3/C3a受体（C3aR）通路在神经退行性疾病和自身免疫性疾病，尤其是视神经脊髓炎谱系疾病（NMOSD）的发病机制中起关键作用。尽管如此，C3/C3aR通路在NMOSD中的具体致病作用和机制仍不清楚。在本研究中，我们首次证明在NMOSD相关视神经炎（NMOSD-ON）大鼠模型的视神经中，C3aR及其上游配体C3的表达显著上调。我们的研究结果表明，这种上调会导致血脑屏障（BBB）破坏、脱髓鞘和神经元损伤。通过使用一种新型的C3aR抑制剂JR14a，我们证明了它在降低C3aR表达和减轻视神经病理损伤方面的有效性。此外，我们对NMOSD视神经组织的转录组测序分析揭示了炎症和免疫反应相关通路的广泛富集，尤其着重于补体和凝血级联反应通路。本研究不仅阐明了C3-C3aR通路在NMOSD-ON发病机制中的关键作用，还通过抑制C3aR通路为NMOSD提供了一个新的有前景的治疗靶点。
