Pharmacology and Toxicology Section, Pharmaceutical Institute, University of Bonn, 53121, Bonn, Germany.
Cell Commun Signal. 2023 Nov 23;21(1):335. doi: 10.1186/s12964-023-01356-1.
The purinergic receptor P2X7 plays a crucial role in infection, inflammation, and cell death. It is thought that P2X7 receptor stimulation triggers processing and release of the pro-inflammatory cytokine interleukin (IL)-1β by activation of the NLRP3 inflammasome; however, the underlying mechanisms remain poorly understood.
Modulation of IL-1β secretion was studied in THP-1 macrophages. Adenosine 5'-triphosphate (ATP), BzATP, nigericin and pharmacological inhibitors of P2X receptors, inflammatory caspases and the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome were used to characterize signaling.
In primed macrophages, IL-1β release was increased after P2X7 receptor activation by ATP and 2,3-O-(4-benzoylbenzoyl)-ATP (BzATP). Pharmacological inhibition or genetic knockout of NLRP3 does not completely inhibit IL-1β release in TLR2/1-primed macrophages. Increase in extracellular K as well as inhibition of caspase-1 or serine proteases maintained IL-1β release in macrophages stimulated with P2X7 receptor agonists at 50%.
Our findings suggest a previously unrecognized mechanism of P2X7 receptor mediated IL-1β release and highlight the existence of an NLRP3-independent pathway in human macrophages. Video Abstract.
嘌呤能受体 P2X7 在感染、炎症和细胞死亡中发挥着关键作用。人们认为，P2X7 受体的刺激通过激活 NLRP3 炎性小体触发促炎细胞因子白细胞介素（IL）-1β的加工和释放；然而，其潜在机制仍知之甚少。
研究了 THP-1 巨噬细胞中 IL-1β 的分泌调节。使用腺苷 5'-三磷酸（ATP）、BzATP、 Nigericin 和 P2X 受体、炎性半胱天冬酶和核苷酸结合寡聚结构域样受体家族 Pyrin 结构域包含蛋白 3（NLRP3）炎性小体的药理学抑制剂来表征信号通路。
在经 TLR2/1 预刺激的巨噬细胞中，P2X7 受体被 ATP 和 2,3-O-(4-苯甲酰苯甲酰)-ATP（BzATP）激活后，IL-1β 的释放增加。NLRP3 的药理学抑制或基因敲除并不能完全抑制 TLR2/1 预刺激的巨噬细胞中 IL-1β 的释放。细胞外钾的增加以及半胱天冬酶-1 或丝氨酸蛋白酶的抑制在 50%的情况下维持了 P2X7 受体激动剂刺激的巨噬细胞中 IL-1β 的释放。
我们的发现表明了 P2X7 受体介导的 IL-1β 释放的一种先前未被认识的机制，并强调了人类巨噬细胞中存在一种 NLRP3 非依赖性途径。视频摘要。
