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首页> 外文期刊>Biological chemistry >Kallikrein-related peptidase 6 exacerbates disease in an autoimmune model of multiple sclerosis
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Kallikrein-related peptidase 6 exacerbates disease in an autoimmune model of multiple sclerosis

机译：激肽释放酶相关肽酶6在多发性硬化症的自身免疫模型中加剧疾病

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Kallikrein-related peptidase 6 (Klk6) is elevated in the serum of multiple sclerosis (MS) patients and is hypothesized to participate in inflammatory and neuropathogenic aspects of the disease. To test this hypothesis, we investigated the impact of systemic administration of recombinant Klk6 on the development and progression of MOG35-55-induced experimental autoimmune encephalomyelitis (EAE). First, we determined that Klk6 expression is elevated in the spinal cord of mice with EAE at the peak of clinical disease and in immune cells upon priming with the disease-initiating peptide in vitro. Systemic administration of recombinant Klk6 to mice during the priming phase of disease resulted in an exacerbation of clinical symptoms, including earlier onset of disease and higher levels of spinal cord inflammation and pathology. Treatment of MOG35-55-primed immune cells with Klk6 in culture enhanced expression of proinflammatory cytokines, interferon-gamma, tumor necrosis factor, and -interleukin-17, while reducing anti-inflammatory cytokines interleukin-4 and interleukin-5. Together these findings provide evidence that elevations in systemic Klk6 can bias the immune system towards pro-inflammatory responses capable of exacerbating the development of neuroinflammation and paralytic neurological deficits. We suggest that Klk6 represents an important target for conditions in which pro-inflammatory responses play a critical role in disease development, including MS.
机译：激肽释放酶相关的肽酶6（Klk6）在多发性硬化症（MS）患者的血清中升高，并被假定参与该疾病的炎症和神经致病方面。为了验证该假设，我们研究了系统性施用重组Klk6对MOG35-55诱导的实验性自身免疫性脑脊髓炎（EAE）的发展和进展的影响。首先，我们确定在临床疾病高峰时，EAE小鼠的脊髓中Klk6表达升高，并且在体外用疾病引发肽引发后免疫细胞中Klk6表达升高。在疾病的引发阶段向小鼠全身施用重组Klk6会导致临床症状加重，包括疾病的早期发作以及脊髓炎症和病理学水平更高。在培养物中用Klk6处理以MOG35-55为主的免疫细胞可增强促炎细胞因子，干扰素-γ，肿瘤坏死因子和白细胞介素17的表达，同时减少抗炎细胞因子白细胞介素4和白细胞介素5。这些发现共同提供了证据，表明全身性Klk6升高可将免疫系统偏向促炎反应，从而加剧神经炎症和麻痹性神经功能缺损的发展。我们建议，Klk6代表促炎反应在包括MS在内的疾病发展中起关键作用的疾病的重要靶标。

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