K+ efflux agonists induce NLRP3 inflammasome activation independently of Ca2+ signaling.
K+ efflux agonists induce NLRP3 inflammasome activation independently of Ca2+ signaling.
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DOI：
10.4049/jimmunol.1402658
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发表时间：
2015-04-15
期刊：
影响因子：
--
通讯作者：
Dubyak GR
中科院分区：
文献类型：
--
作者：
Katsnelson MA;Rucker LG;Russo HM;Dubyak GR
细胞内离子稳态的扰动是激活NLRP 3炎性体信号传导的主要细胞应激信号，其导致半胱天冬酶-1介导的IL-1β产生和细胞凋亡。然而，细胞内[K+]减少与细胞内[Ca 2 +]增加的相对贡献仍然存在争议和不完全定义。我们研究了两种典型的NLRP 3激动剂（ATP和尼日利亚菌素）通过不同的机制途径或溶酶体去稳定激动剂Leu-Leu-O-甲酯（LLME）促进初级K+外流时，原代小鼠树突状细胞和巨噬细胞中NLRP 3激活和下游炎性体信号传导反应中胞浆[Ca 2 +]升高的作用。该研究提供了与NLRP 3调节的未解决领域相关的三个主要发现。首先，增加胞质[Ca 2 +]既不是必要的，也不是足够的信号NLRP 3炎症级联过程中激活内源性ATP门控P2 X7受体通道，外源性细菌离子载体尼日利亚菌素，或lysosomotropic剂LLME。第二，激动剂的三个钙动员G蛋白偶联受体（甲酰肽受体/FPR; P2 Y2嘌呤受体/P2 Y2 R;钙敏感受体/CaSR）表达的小鼠树突状细胞是无效的快速诱导NLRP 3信号的激活剂时，直接比较K+外排激动剂。第三，细胞内Ca 2+缓冲剂BAPTA和通道阻断剂2-氨基乙氧基二苯基硼酸酯（2-APB），广泛用于破坏Ca 2+依赖性信号传导途径的试剂，通过与其对Ca 2+稳态的典型或预期作用分离的机制强烈抑制尼日利亚菌素诱导的NLRP 3炎性体信号传导。结果表明，K+外排激动剂激活NLRP 3炎性体信号传导的能力可以与细胞溶质[Ca 2 +]的变化分离，作为必要或充分的信号。
Perturbation of intracellular ion homeostasis is a major cellular stress signal for activation of NLRP3 inflammasome signaling that results in caspase-1 mediated production of IL-1β and pyroptosis. However, the relative contributions of decreased cytosolic [K+] versus increased cytosolic [Ca2+] remain disputed and incompletely defined. We investigated roles for elevated cytosolic [Ca2+] in NLRP3 activation and downstream inflammasome signaling responses in primary murine dendritic cells and macrophages in response to two canonical NLRP3 agonists (ATP and nigericin) that facilitate primary K+ efflux by mechanistically distinct pathways or the lysosome-destabilizing agonist Leu-Leu-O-methyl ester (LLME). The study provides three major findings relevant to this unresolved area of NLRP3 regulation. First, increased cytosolic [Ca2+] was neither a necessary nor sufficient signal for the NLRP3 inflammasome cascade during activation by endogenous ATP-gated P2X7 receptor channels, the exogenous bacterial ionophore nigericin, or the lysosomotropic agent LLME. Second, agonists for three Ca2+-mobilizing G protein-coupled receptors (formyl peptide receptor/FPR; P2Y2 purinergic receptor/P2Y2R; calcium-sensing receptor/CaSR) expressed in murine dendritic cells were ineffective as activators of rapidly induced NLRP3 signaling when directly compared to the K+ efflux agonists. Third, the intracellular Ca2+ buffer, BAPTA, and the channel blocker, 2-aminoethoxydiphenyl borate (2-APB), widely used reagents for disruption of Ca2+-dependent signaling pathways, strongly suppressed nigericin-induced NLRP3 inflammasome signaling via mechanisms dissociated from their canonical or expected effects on Ca2+ homeostasis. The results indicate that the ability of K+ efflux agonists to activate NLRP3 inflammasome signaling can be dissociated from changes in cytosolic [Ca2+] as a necessary or sufficient signal.
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