Pharmacological inhibition of Kv1.3 channel impairs TLR3/4 activation and type I IFN response and confers protection against Listeria monocytogenes infection. (March 2022)

• Record Type: Journal Article
• Authors: Zhang, Xin; Lin, Xiulin; Luo, Hui; Zhi, Yuanxing; Yi, Xin; Wu, Xiaoyan; Duan, Wendi; Cao, Ying; Pang, Jianxin; Liu, Shuwen; Zhou, Pingzheng
• Is Part Of: Pharmacological research. Volume 177(2022)
• Publication Date: 2022-03
• Subjects: Voltage-gated potassium channel -- Interferon -- Toll receptor -- Kv channel -- Innate immunity; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2022.106112
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: 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 against Listeria monocytogenes induced 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. Graphical Abstract: Title: PAP-1 suppressed TLR3/4-induced type I IFN signal transduction ga1