Kallikrein 6 regulates early CNS demyelination in a viral model of multiple sclerosis.
Kallikrein 6 regulates early CNS demyelination in a viral model of multiple sclerosis.
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DOI：
10.1111/j.1750-3639.2012.00577.x
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发表时间：
2012-09
期刊：
影响因子：
--
通讯作者：
Rodriguez M
中科院分区：
文献类型：
--
作者：
Scarisbrick IA;Yoon H;Panos M;Larson N;Blaber SI;Blaber M;Rodriguez M
激肽释放酶6（Klk6）是一种分泌的丝氨酸蛋白酶，其在活动性多发性硬化病变和患者血清中升高。为了进一步评估Klk6在慢性进行性脱髓鞘疾病中的参与，我们测定了其在感染Theiler小鼠脑脊髓炎病毒（TMEV）的SJL小鼠的脑和脊髓中的表达，并评估了Klk6中和抗体对疾病进展的影响。Klk6 RNA表达在感染后7天（dpi）在脑和脊髓中升高。此后，Klk6表达主要持续在脊髓中，在慢性中期（60 - 120 dpi）达到对照的5倍的峰值。在体外用病毒衣壳蛋白刺激的脾细胞和活化的THP-1单核细胞中也诱导Klk6 RNA显著升高。当在早期慢性时间点（40 dpi）检查时，Klk6中和抗体减少TMEV驱动的脑和脊髓病理学和DTH反应。脊髓病理学的减少包括活化的单核细胞/小胶质细胞减少和髓鞘碱性蛋白（MBP）丢失减少。到180 dpi时，各组之间的病理学评分不再存在差异。这些发现指出Klk6在CNS炎症和脱髓鞘的发展和进展中的调节活性，其可以通过中和抗体的早期慢性阶段有效地靶向。
Kallikrein 6 (Klk6) is a secreted serine protease that is elevated in active multiple sclerosis lesions and patient sera. To further evaluate the involvement of Klk6 in chronic progressive demyelinating disease, we determined its expression in the brain and spinal cord of SJL mice infected with Theiler’s murine encephalomyelitis virus (TMEV) and assessed the effects of Klk6-neutralizing antibodies on disease progression. Klk6 RNA expression was elevated in the brain and spinal cord by 7 days post-infection (dpi). Thereafter, Klk6 expression persisted primarily in the spinal cord reaching a peak of 5-fold over controls at mid-chronic stages (60–120 dpi). Significant elevations in Klk6 RNA were also induced in splenocytes stimulated with viral capsid proteins in vitro and in activated THP-1 monocytes. Klk6-neutralizing antibodies reduced TMEV-driven brain and spinal cord pathology and DTH responses when examined at early chronic time points (40 dpi). Reductions in spinal cord pathology included a decrease in activated monocytes/microglia and reductions in the loss of myelin basic protein (MBP). By 180 dpi, pathology scores no longer differed between groups. These findings point to regulatory activities for Klk6 in the development and progression of CNS inflammation and demyelination that can be effectively targeted through the early chronic stages with neutralizing antibody.
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