Zhu Huimin, Wang Ningning, Chang Yingying, Zhang Ying, Jiang Shihe, Ren Xiaoping, Yuan Meng, Chang Haoxiao, Jin Wei-Na
Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China.
The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Stroke Vasc Neurol. 2025 Jun 30;10(3):347-358. doi: 10.1136/svn-2024-003525.
Intracerebral haemorrhage (ICH) elicits a robust inflammatory response, which significantly contributes to secondary brain damage. Extracellular vesicles (EVs) play a pivotal role in intercellular communication by transporting immune-regulatory proteins. However, the precise contribution of these EV-carried proteins to neuroinflammation following ICH remains elusive. Here, we identified proteins dysregulated in EVs and further studied the EVs-enriched Serum amyloid A 1 (SAA1) to understand its role in neuroinflammation and ICH injury.
We used mass spectrometry to analyse the EV protein cargo isolated from plasma samples of 30 ICH patients and 30 healthy controls. To validate the function of the dysregulated protein SAA1, an ICH mouse model was conducted to assess the effects of SAA1 neutralisation on brain oedema, neurological function and infiltration of peripheral leucocytes.
49 upregulated proteins and 12 downregulated proteins were observed in EVs from ICH patients compared with controls. Notably, SAA1 demonstrated a significant increase in EVs associated with ICH. We observed that exogenous SAA1 stimulation led to an augmentation in the population of microglia and astrocytes, exacerbating neuroinflammation. Neutralising SAA1 with an anti-SAA1 monoclonal antibody (mAb) diminished the prevalence of proinflammatory microglia and the infiltration of peripheral leucocytes, which ameliorates brain oedema and neurological function in ICH mice.
Our findings provide compelling evidence implicating EVs and their cargo proteins in ICH pathogenesis. SAA1 emerges as a potential therapeutic target for mitigating neuroinjury and neuroinflammation following ICH.
脑出血（ICH）引发强烈的炎症反应，这对继发性脑损伤有显著影响。细胞外囊泡（EVs）通过运输免疫调节蛋白在细胞间通讯中发挥关键作用。然而，这些由EVs携带的蛋白对脑出血后神经炎症的确切作用仍不清楚。在此，我们鉴定了EVs中失调的蛋白，并进一步研究了富含EVs的血清淀粉样蛋白A1（SAA1），以了解其在神经炎症和脑出血损伤中的作用。
我们使用质谱分析从30例脑出血患者和30例健康对照的血浆样本中分离出的EV蛋白成分。为了验证失调蛋白SAA1的功能，构建了脑出血小鼠模型，以评估中和SAA1对脑水肿、神经功能和外周白细胞浸润的影响。
与对照组相比，在脑出血患者的EVs中观察到49种上调蛋白和12种下调蛋白。值得注意的是，SAA1在与脑出血相关的EVs中显著增加。我们观察到外源性SAA1刺激导致小胶质细胞和星形胶质细胞数量增加，加剧了神经炎症。用抗SAA1单克隆抗体（mAb）中和SAA1可减少促炎性小胶质细胞的数量和外周白细胞的浸润，从而改善脑出血小鼠的脑水肿和神经功能。
我们的研究结果提供了令人信服的证据，表明EVs及其携带的蛋白参与了脑出血的发病机制。SAA1成为减轻脑出血后神经损伤和神经炎症的潜在治疗靶点。
