IRAK-M deficiency exacerbates dopaminergic neuronal damage in a mouse model of sub-acute Parkinson’s disease
IRAK-M deficiency exacerbates dopaminergic neuronal damage in a mouse model of sub-acute Parkinson’s disease
复制标题
DOI：
10.1097/wnr.0000000000001913
复制
发表时间：
2023-04
期刊：
影响因子：
1.7
通讯作者：
Yi-dong Deng;Yuangao Liao;Peijian Huang;Yujian Yao;Weihua Liu;Yong Gu;Guohu Weng
中科院分区：
文献类型：
--
作者：
Yi-dong Deng;Yuangao Liao;Peijian Huang;Yujian Yao;Weihua Liu;Yong Gu;Guohu Weng
新的证据证明炎症反应会加剧帕金森病的病理进展。本研究旨在确定白细胞介素 1 受体相关激酶 M (IRAK-M) 作为先天免疫的重要负调节因子在帕金森病病理进展中的作用。本研究采用1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）注射液制备急性和亚急性帕金森病小鼠模型。 Western blot分析用于检测酪氨酸羟化酶和IRAK-M的蛋白表达。通过逆转录定量PCR (RT-qPCR) 评估IRAK-M、白细胞介素(IL)-6、IL-β 和环氧合酶-2 的mRNA 表达水平。采用免疫组织化学法检测纹状体和黑质致密部（SNc）组织中酪氨酸羟化酶阳性神经元的表达。结果显示，亚急性帕金森病模型中纹状体和 SNc 组织中 IRAK-M 的蛋白和 mRNA 水平显着上调。此外，IRAK-M敲除显着增强了MPTP诱导的纹状体中酪氨酸羟化酶阳性纤维和SNc中酪氨酸羟化酶阳性神经元的损失，并增强了MPTP对小胶质细胞活化和炎性细胞因子表达的影响。此外，IRAK-M缺失的亚急性帕金森病小鼠表现出比野生型同窝小鼠更差的运动能力。总体而言，本研究表明IRAK-M通过抑制炎症来减少亚急性帕金森病的多巴胺能神经元损伤，这可能为帕金森病的治疗提供新的治疗靶点。
Emerging evidence has proved that inflammatory responses aggravate the pathological progression of Parkinson’s disease. This study aimed to identify the role of Interleukin-1 receptor-associated kinase-M (IRAK-M) as an important negative regulator of innate immunity, in the pathological progression of Parkinson’s disease. In the present study, a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injection was administered to prepare the acute and sub-acute Parkinson’s disease mouse models. Western blot analysis was utilized to examine the protein expressions of tyrosine hydroxylase and IRAK-M. The mRNA expression levels of IRAK-M, interleukin (IL)-6, IL-β, and cyclooxygenase-2 were evaluated via using reverse transcription quantitative PCR (RT-qPCR). The expression of tyrosine hydroxylase-positive neurons in corpus striatum and substantia nigra pars compacta (SNc) tissues was detected using immunohistochemistry. The results showed that the protein and mRNA levels of IRAK-M were considerably upregulated in corpus striatum and SNc tissues in the sub-acute Parkinson’s disease model. Furthermore, IRAK-M knockout significantly enhanced the MPTP-induced loss of tyrosine hydroxylase-positive fibers in corpus striatum and tyrosine hydroxylase-positive neurons in SNc, and intensified the effect of MPTP on the activation of microglial cells and the expression of inflammatory cytokines. In addition, sub-acute Parkinson’s disease mice with IRAK-M deletion exhibited worse motor abilities than those of wild-type littermates. Overall, the present study suggested that IRAK-M reduces dopaminergic neuron damage in sub-acute Parkinson’s disease by suppressing inflammation, which may provide a new therapeutic target for Parkinson’s disease treatment.