Biglycan, a Danger Signal That Activates the NLRP3 Inflammasome via Toll-like and P2X Receptors
Biglycan, a Danger Signal That Activates the NLRP3 Inflammasome via Toll-like and P2X Receptors
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DOI：
10.1074/jbc.m109.014266
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发表时间：
2009-09-04
影响因子：
4.8
通讯作者：
Schaefer, Liliana
中科院分区：
文献类型：
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作者：
Babelova, Andrea;Moreth, Kristin;Schaefer, Liliana
炎症的内源性诱导物的作用了解甚少。为了产生促炎性主要细胞因子白细胞介素（IL）-1β，巨噬细胞需要用配体对Toll样受体（TLRs）进行双重刺激以实现IL - 1β基因转录，并需要用配体对核苷酸结合寡聚化结构域样受体进行刺激以激活炎症小体。在没有感染触发因素的情况下，这种复杂的调节是如何介导的，这一点尤其令人感兴趣。双糖链蛋白聚糖是细胞外基质中一种普遍存在的富含亮氨酸重复序列的蛋白聚糖，它与巨噬细胞上的TLR2/4相互作用。本研究的目的是确定双糖链蛋白聚糖在IL - 1β的合成和激活中的作用。在此我们表明，在巨噬细胞中，可溶性双糖链蛋白聚糖可诱导NLRP3/ASC炎症小体，激活半胱天冬酶 - 1并释放成熟的IL - 1β，而无需额外的共刺激因子。这是通过双糖链蛋白聚糖与TLR2/4和嘌呤能P2X(4)/P2X7受体的相互作用实现的，这种相互作用诱导了受体协同性。此外，活性氧的形成参与了双糖链蛋白聚糖介导的炎症小体激活。通过TLR2/4发出信号，双糖链蛋白聚糖刺激NLRP3和proIL - 1β mRNA的表达。在非感染性炎症性肾损伤（单侧输尿管梗阻）模型和脂多糖诱导的脓毒症中，双糖链蛋白聚糖缺陷型小鼠在肾脏、肺和循环中表现出较低水平的活性半胱天冬酶 - 1和成熟的IL - 1β。我们的研究结果为双糖链蛋白聚糖直接激活NLRP3炎症小体提供了证据，并描述了一个基本范例，即固有免疫受体如何通过检测细胞外基质成分的释放来监测组织应激或损伤，并将这种信号转化为强烈的炎症反应。
The role of endogenous inducers of inflammation is poorly understood. To produce the proinflammatory master cytokine interleukin (IL)-1 beta, macrophages need double stimulation with ligands to both Toll-like receptors (TLRs) for IL-1 beta gene transcription and nucleotide-binding oligomerization domain-like receptors for activation of the inflammasome. It is particularly intriguing to define how this complex regulation is mediated in the absence of an infectious trigger. Biglycan, a ubiquitous leucine-rich repeat proteoglycan of the extracellular matrix, interacts with TLR2/4 on macrophages. The objective of this study was to define the role of biglycan in the synthesis and activation of IL-1 beta. Here we show that in macrophages, soluble biglycan induces the NLRP3/ASC inflammasome, activating caspase-1 and releasing mature IL-1 beta without the need for additional costimulatory factors. This is brought about by the interaction of biglycan with TLR2/4 and purinergic P2X(4)/P2X7 receptors, which induces receptor cooperativity. Furthermore, reactive oxygen species formation is involved in biglycan-mediated activation of the inflammasome. By signaling through TLR2/4, biglycan stimulates the expression of NLRP3 and proIL-1 beta mRNA. Both in a model of non-infectious inflammatory renal injury (unilateral ureteral obstruction) and in lipopolysaccharide-induced sepsis, biglycan-deficient mice displayed lower levels of active caspase-1 and mature IL-1 beta in the kidney, lung, and circulation. Our results provide evidence for direct activation of the NLRP3 inflammasome by biglycan and describe a fundamental paradigm of how tissue stress or injury is monitored by innate immune receptors detecting the release of the extracellular matrix components and turning such a signal into a robust inflammatory response.