Institute of Neurophysiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117, Berlin, Germany.
Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany.
J Neuroinflammation. 2024 Feb 26;21(1):58. doi: 10.1186/s12974-024-03042-6.
Neuroinflammation is highly influenced by microglia, particularly through activation of the NLRP3 inflammasome and subsequent release of IL-1β. Extracellular ATP is a strong activator of NLRP3 by inducing K efflux as a key signaling event, suggesting that K-permeable ion channels could have high therapeutic potential. In microglia, these include ATP-gated THIK-1 K channels and P2X7 receptors, but their interactions and potential therapeutic role in the human brain are unknown. Using a novel specific inhibitor of THIK-1 in combination with patch-clamp electrophysiology in slices of human neocortex, we found that THIK-1 generated the main tonic K conductance in microglia that sets the resting membrane potential. Extracellular ATP stimulated K efflux in a concentration-dependent manner only via P2X7 and metabotropic potentiation of THIK-1. We further demonstrated that activation of P2X7 was mandatory for ATP-evoked IL-1β release, which was strongly suppressed by blocking THIK-1. Surprisingly, THIK-1 contributed only marginally to the total K conductance in the presence of ATP, which was dominated by P2X7. This suggests a previously unknown, K-independent mechanism of THIK-1 for NLRP3 activation. Nuclear sequencing revealed almost selective expression of THIK-1 in human brain microglia, while P2X7 had a much broader expression. Thus, inhibition of THIK-1 could be an effective and, in contrast to P2X7, microglia-specific therapeutic strategy to contain neuroinflammation.
神经炎症受小胶质细胞的高度影响，特别是通过 NLRP3 炎性体的激活和随后的 IL-1β 释放。细胞外 ATP 通过诱导 K 外流作为关键信号事件强烈激活 NLRP3，这表明 K 渗透性离子通道可能具有很高的治疗潜力。在小胶质细胞中，这些包括 ATP 门控 THIK-1 K 通道和 P2X7 受体，但它们的相互作用及其在人脑中的潜在治疗作用尚不清楚。我们使用一种新型的 THIK-1 特异性抑制剂，结合人类新皮质切片的膜片钳电生理学，发现 THIK-1 在小胶质细胞中产生主要的紧张性 K 电导，从而设定静息膜电位。细胞外 ATP 通过 P2X7 和 THIK-1 的代谢增强以浓度依赖性方式刺激 K 外流。我们进一步证明，P2X7 的激活对于 ATP 诱导的 IL-1β 释放是必需的，而阻断 THIK-1 则强烈抑制了这一过程。令人惊讶的是，THIK-1 在存在 ATP 的情况下对总 K 电导的贡献仅微不足道，而 P2X7 则占主导地位。这表明了 THIK-1 激活 NLRP3 的一种以前未知的、与 K 无关的机制。核测序显示，THIK-1 在人类大脑小胶质细胞中几乎选择性表达，而 P2X7 则有更广泛的表达。因此，抑制 THIK-1 可能是一种有效的、与 P2X7 相反的、针对小胶质细胞的神经炎症控制治疗策略。
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