Pharmacological inhibition of Kv1.3 channel impairs TLR3/4 activation and type I IFN response and confers protection against Listeria monocytogenes infection.
Pharmacological inhibition of Kv1.3 channel impairs TLR3/4 activation and type I IFN response and confers protection against Listeria monocytogenes infection.
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DOI：
10.1016/j.phrs.2022.106112
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发表时间：
2022-02
影响因子：
9.3
通讯作者：
Xin Zhang;Xiuling Lin;H. Luo;Yuanxing Zhi;X. Yi;Xiaoyan Wu;Wendi Duan;Ying Cao;Jianxin Pang;Shuwen Liu;Pingzheng Zhou
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作者：
Xin Zhang;Xiuling Lin;H. Luo;Yuanxing Zhi;X. Yi;Xiaoyan Wu;Wendi Duan;Ying Cao;Jianxin Pang;Shuwen Liu;Pingzheng Zhou
新出现的数据已经证明了钾外排在先天免疫系统中的关键作用。然而，钾外排在TLR3/4激活和I型干扰素（IFN）应答中的作用尚未得到很好的阐明。在本研究中，我们发现钾外排是介导IFN及其诱导基因Cxcl10和促炎细胞因子基因TNF-α表达的TLR3/4信号通路的关键。此外，药物抑制Kv1.3通道（PAP-1），而不是Kir2.1、KCa3.1或TWIK2，可以减弱巨噬细胞中TLR3/4受体的激活。在机制上，PAP-1通过显著抑制JNK丝裂原活化蛋白激酶（MAPK）和核因子- kb (NF-kB) p65亚基的激活来抑制lps诱导的炎症功能。值得注意的是，PAP-1可以有效地保护小鼠免受单核细胞增生李斯特菌诱导的感染。我们的研究结果表明，Kv1.3通道介导的钾外排对TLR3/4激活至关重要，并提示Kv1.3的药理抑制可能有助于治疗I型IFN相关的自身免疫性疾病和细菌感染。
Emerging data have demonstrated the critical roles of potassium efflux in the innate immune system. However, the role of potassium efflux in TLR3/4 activation and type I interferon (IFN) responses are not well elucidated. In the present study, we found potassium efflux is essential for TLR3/4 signaling, which mediates the expression of IFN and its inducible gene Cxcl10 and proinflammatory cytokine gene TNF-α. Furthermore, pharmacological inhibition of Kv1.3 channel (PAP-1), but not Kir2.1, KCa3.1 or TWIK2, attenuated TLR3/4 receptor activation in macrophages. Mechanistically, PAP-1 suppressed LPS-induced inflammatory function through marked suppressing the activation of JNK mitogen-activated protein kinase (MAPK) and p65 subunit of nuclear factor-kB (NF-kB). Notably, PAP-1 effectively protected mice againstListeria monocytogenesinduced infection. Our findings reveal that potassium efflux mediated by the Kv1.3 channel is essential for TLR3/4 activation and suggest that pharmacological inhibition of Kv1.3 may help to treat type I IFN related autoimmune diseases and bacterial infections.