Adeno-associated Virus Vector-mediated Interleukin-10 Induction Prevents Vascular Inflammation in a Murine Model of Kawasaki Disease.
Adeno-associated Virus Vector-mediated Interleukin-10 Induction Prevents Vascular Inflammation in a Murine Model of Kawasaki Disease.
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DOI：
10.1038/s41598-018-25856-0
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发表时间：
2018-05-15
影响因子：
4.6
通讯作者：
Takahashi M
中科院分区：
文献类型：
--
作者：
Nakamura J;Watanabe S;Kimura H;Kobayashi M;Karasawa T;Kamata R;Usui-Kawanishi F;Sadatomo A;Mizukami H;Nagi-Miura N;Ohno N;Kasahara T;Minota S;Takahashi M
川崎是小儿心脏病的主要病因，以冠状血管炎和随后的动脉瘤形成为特征。虽然静脉注射免疫球蛋白治疗对减少动脉瘤形成有效，但一定数量的患者对这种治疗有抵抗力。由于白细胞介素-10（IL-10）被鉴定为白色念珠菌水溶性组分（CAWS）诱导的KD小鼠模型中心脏炎症的负调节因子，因此我们研究了补充IL-10对CAWS诱导的血管炎的影响。将编码IL-10的腺相关病毒（AAV）载体肌肉内注射小鼠，然后用CAWS处理。腺相关病毒介导的白细胞介素-10（AAV-IL-10）的诱导可显著减轻主动脉根部和冠状动脉中的血管炎症和纤维化，从而改善心功能障碍和致死性。血管壁中主要浸润的炎症细胞是Dectin-2+ CD 11b+巨噬细胞。体外实验表明，粒细胞/巨噬细胞集落刺激因子（GM-CSF）可诱导骨髓源性巨噬细胞表达Dectin-2，并增强CAWS诱导的肿瘤坏死因子-α（TNF-α）和IL-6的产生。IL-10对Dectin-2的表达没有影响，但显著抑制细胞因子的产生。IL-10还抑制CAWS诱导的ERK 1/2磷酸化，但不抑制Syk。AAV-IL-10的诱导可抑制CAWS诱导的血管炎早期TNF-α和IL-6的表达，但对GM-CSF和Dectin-2的表达无影响。这些发现表明AAV-IL-10可能在预防冠状动脉血管炎和动脉瘤形成中具有治疗应用，并为KD发病机制提供新的见解。
Kawasaki disease (KD), which is the leading cause of pediatric heart disease, is characterized by coronary vasculitis and subsequent aneurysm formation. Although intravenous immunoglobulin therapy is effective for reducing aneurysm formation, a certain number of patients are resistant to this therapy. Because interleukin-10 (IL-10) was identified as a negative regulator of cardiac inflammation in a murine model of KD induced by Candida albicans water-soluble fraction (CAWS), we investigated the effect of IL-10 supplementation in CAWS-induced vasculitis. Mice were injected intramuscularly with adeno-associated virus (AAV) vector encoding IL-10, then treated with CAWS. The induction of AAV-mediated IL-10 (AAV-IL-10) significantly attenuated the vascular inflammation and fibrosis in the aortic root and coronary artery, resulting in the improvement of cardiac dysfunction and lethality. The predominant infiltrating inflammatory cells in the vascular walls were Dectin-2+CD11b+ macrophages. In vitro experiments revealed that granulocyte/macrophage colony-stimulating factor (GM-CSF) induced Dectin-2 expression in bone marrow-derived macrophages and enhanced the CAWS-induced production of tumor necrosis factor-α (TNF-α) and IL-6. IL-10 had no effect on the Dectin-2 expression but significantly inhibited the production of cytokines. IL-10 also inhibited CAWS-induced phosphorylation of ERK1/2, but not Syk. Furthermore, the induction of AAV-IL-10 prevented the expression of TNF-α and IL-6, but not GM-CSF and Dectin-2 at the early phase of CAWS-induced vasculitis. These findings demonstrate that AAV-IL-10 may have therapeutic application in the prevention of coronary vasculitis and aneurysm formation, and provide new insights into the mechanism underlying the pathogenesis of KD.
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影响因子：
7.3
作者：
Ng TH;Britton GJ;Hill EV;Verhagen J;Burton BR;Wraith DC
通讯作者：
Wraith DC
影响因子：
3.8
作者：
Saxena, Ankit;Khosraviani, Sam;Noel, Sanjeev;Mohan, Divya;Donner, Thomas;Hamad, Abdel Rahim A.
通讯作者：
Hamad, Abdel Rahim A.
影响因子：
5.6
作者：
Dusser P;Koné-Paut I
通讯作者：
Koné-Paut I
影响因子：
3.7
作者：
Kobayashi M;Usui-Kawanishi F;Karasawa T;Kimura H;Watanabe S;Mise N;Kayama F;Kasahara T;Hasebe N;Takahashi M
通讯作者：
Takahashi M
影响因子：
4.4
作者：
Burns JC;Franco A
通讯作者：
Franco A