ADP as a novel stimulus for NLRP3-inflammasome activation in mice fails to translate to humans.

IF 3 4区医学 Q2 NEUROSCIENCES

Purinergic Signalling Pub Date : 2024-06-01 Epub Date: 2023-07-06 DOI:10.1007/s11302-023-09953-y

Julius Wissemann, Adrian Heidenreich, Helene Zimmermann, Juliane Engelmann, Jasper Jansen, Dymphie Suchanek, Dirk Westermann, Dennis Wolf, Peter Stachon, Julian Merz

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引用次数: 0

Abstract

The NLRP3-inflammasome is a cytosolic multiprotein complex that triggers an inflammatory response to certain danger signals. Recently adenosine diphosphate (ADP) was found to activate the NLRP3-inflammasome in murine macrophages via the P2Y₁ receptor. Blockade of this signaling pathway reduced disease severity in a murine colitis-model. However, the role of the ADP/P2Y₁-axis has not yet been studied in humans. This present study confirmed ADP-dependent NLRP3-inflammasome activation in murine macrophages, but found no evidence for a role of ADP in inflammasome activation in humans. We investigated the THP1 cell line as well as primary monocytes and further looked at macrophages. Although all cells express the three human ADP-receptors P2Y₁, P2Y₁₂ and P2Y₁₃, independent of priming, neither increased ASC-speck formation could be detected with flow cytometry nor additional IL-1β release be found in the culture supernatant of ADP stimulated cells. We now show for the first time that the responsiveness of monocytes and macrophages to ADP as well as the regulation of its purinergic receptors is very much dependent on the species. Therefore the signaling pathway found to contribute to colitis in mice is likely not applicable to humans.

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ADP 作为激活小鼠 NLRP3-炎症小体的一种新型刺激物未能转化为人类的刺激物。

NLRP3-炎症小体是一种细胞膜多蛋白复合物，可触发对某些危险信号的炎症反应。最近发现，二磷酸腺苷（ADP）可通过 P2Y1 受体激活小鼠巨噬细胞中的 NLRP3-炎症体。在小鼠结肠炎模型中，阻断这一信号通路可减轻疾病的严重程度。然而，ADP/P2Y1 轴在人体中的作用尚未得到研究。本研究证实了小鼠巨噬细胞中依赖 ADP 的 NLRP3-炎症小体活化，但没有发现 ADP 在人类炎症小体活化中发挥作用的证据。我们研究了 THP1 细胞系和原代单核细胞，并进一步研究了巨噬细胞。虽然所有细胞都表达了三种人类 ADP 受体 P2Y1、P2Y12 和 P2Y13，但与引物无关，流式细胞术既不能检测到 ASC 斑形成的增加，也不能在 ADP 刺激细胞的培养上清液中发现 IL-1β 的额外释放。我们现在首次证明，单核细胞和巨噬细胞对 ADP 的反应性及其嘌呤能受体的调节在很大程度上取决于物种。因此，在小鼠体内发现的导致结肠炎的信号通路很可能不适用于人类。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Purinergic Signalling 医学-神经科学

CiteScore

6.60

自引率

17.10%

发文量

审稿时长

6-12 weeks

期刊介绍： Nucleotides and nucleosides are primitive biological molecules that were utilized early in evolution both as intracellular energy sources and as extracellular signalling molecules. ATP was first identified as a neurotransmitter and later as a co-transmitter with all the established neurotransmitters in both peripheral and central nervous systems. Four subtypes of P1 (adenosine) receptors, 7 subtypes of P2X ion channel receptors and 8 subtypes of P2Y G protein-coupled receptors have currently been identified. Since P2 receptors were first cloned in the early 1990’s, there is clear evidence for the widespread distribution of both P1 and P2 receptor subtypes in neuronal and non-neuronal cells, including glial, immune, bone, muscle, endothelial, epithelial and endocrine cells.