Kallikrein-related peptidase 6 exacerbates disease in an autoimmune model of multiple sclerosis.
Kallikrein-related peptidase 6 exacerbates disease in an autoimmune model of multiple sclerosis.
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DOI：
10.1515/hsz-2016-0239
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发表时间：
2016-12-01
影响因子：
3.7
通讯作者：
Scarisbrick IA
中科院分区：
文献类型：
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作者：
Yoon H;Scarisbrick IA
多发性硬化症（MS）患者血清中钾化肽相关肽酶6 （Klk6）升高，并被假设参与该疾病的炎症和神经致病方面。为了验证这一假设，我们研究了重组Klk6对mog35 -55诱导的实验性自身免疫性脑脊髓炎（EAE）发生和进展的影响。首先，我们确定在临床疾病高峰期，EAE小鼠脊髓中的Klk6表达升高，在体外用疾病启动肽启动免疫细胞时，Klk6表达升高。在疾病启动阶段对小鼠全身给予重组Klk6导致临床症状加重，包括疾病发作更早，脊髓炎症和病理水平更高。用Klk6处理mog35 -55引物培养的免疫细胞可增强促炎因子、干扰素-γ、肿瘤坏死因子和白细胞介素-17的表达，同时降低抗炎因子白细胞介素-4和白细胞介素-5的表达。总之，这些发现提供了证据，表明全身性Klk6的升高可以使免疫系统偏向于能够加剧神经炎症和麻痹性神经功能缺陷的促炎反应。我们认为，Klk6是促炎反应在包括MS在内的疾病发展中起关键作用的一个重要靶点。
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-γ, 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.