Soluble CD36 ectodomain binds negatively charged diacylglycerol ligands and acts as a co-receptor for TLR2.
Soluble CD36 ectodomain binds negatively charged diacylglycerol ligands and acts as a co-receptor for TLR2.
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DOI：
10.1371/journal.pone.0007411
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发表时间：
2009-10-22
期刊：
影响因子：
3.7
通讯作者：
Wilson IA
中科院分区：
文献类型：
--
作者：
Jimenez-Dalmaroni MJ;Xiao N;Corper AL;Verdino P;Ainge GD;Larsen DS;Painter GF;Rudd PM;Dwek RA;Hoebe K;Beutler B;Wilson IA
分化抗原36（CD36）是一种跨膜糖蛋白，参与血小板生物学、血管生成、动脉粥样硬化和心血管疾病等多种生物学过程。Toll样受体（TLR）是先天免疫系统中最重要的受体之一。它们的主要功能是识别微生物的保守结构。这种识别触发信号传导途径，其激活细胞因子和共刺激分子的转录，所述细胞因子和共刺激分子参与产生针对微生物的免疫应答。特别是，TLR2已被证明识别广泛的配体。最近，我们发现，CD36作为TLR2的共受体，并增强识别特定的二酰甘油酯来源于细菌。在这里，我们研究的机制，CD36有助于配体识别和激活TLR2信号通路。我们发现，鼠CD36（mCD36ED）的胞外域直接与带负电荷的二酰基甘油配体相互作用，这解释了CD36作为TLR2共受体的特异性和选择性。我们还表明，mCD36ED放大了野生型小鼠巨噬细胞中对脂磷壁酸的促炎反应，并恢复了CD36缺陷小鼠（不经意）巨噬细胞的促炎反应，但没有恢复分化簇14（CD14）缺陷小鼠（不经意）的促炎反应。这些数据表明，CD36胞外域是激活TLR2信号传导途径的唯一相关结构域，并且CD36和CD14在将配体装载到质膜中的TLR2上方面具有非冗余作用。可溶性CD36的促炎作用可能与激活针对病原体的免疫应答以及慢性疾病的进展有关。因此，可溶性形式的CD36的水平增加（已报道其在II型糖尿病患者中增加）可通过增加对二酰基甘油配体的促炎反应来加速动脉粥样硬化。
Cluster of differentiation 36 (CD36) is a transmembrane glycoprotein involved in many biological processes, such as platelet biology, angiogenesis and in the aetiopathology of atherosclerosis and cardiovascular diseases. Toll-like receptors (TLRs) are one of the most important receptors of the innate immune system. Their main function is the recognition of conserved structure of microorganisms. This recognition triggers signaling pathways that activate transcription of cytokines and co-stimulatory molecules which participate in the generation of an immune response against microbes. In particular, TLR2 has been shown to recognize a broad range of ligands. Recently, we showed that CD36 serves as a co-receptor for TLR2 and enhances recognition of specific diacylglycerides derived from bacteria. Here, we investigate the mechanism by which CD36 contributes to ligand recognition and activation of TLR2 signaling pathway. We show that the ectodomain of murine CD36 (mCD36ED) directly interacts with negatively charged diacylglycerol ligands, which explains the specificity and selectivity of CD36 as a TLR2 co-receptor. We also show that mCD36ED amplifies the pro-inflammatory response to lipoteichoic acid in macrophages of wild-type mice and restores the pro-inflammatory response of macrophages from mice deficient in CD36 (oblivious), but not from mice deficient in cluster of differentiation 14 (CD14) (heedless). These data indicate that the CD36 ectodomain is the only relevant domain for activation of TLR2 signaling pathway and that CD36 and CD14 have a non-redundant role for loading ligands onto TLR2 in the plasma-membrane. The pro-inflammatory role of soluble CD36 can be relevant in the activation of the immune response against pathogens, as well as in the progression of chronic diseases. Therefore, an increased level of soluble forms of CD36, which has been reported to be increased in type II diabetic patients, could accelerate atherosclerosis by increasing the pro-inflammatory response to diacylglycerol ligands.
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影响因子：
64.8
作者：
Hoebe, K;Georgel, P;Beutler, B
通讯作者：
Beutler, B
DOI：
10.1073/pnas.94.25.13838
发表时间：
1997-12-09
影响因子：
11.1
作者：
Garcia, KC;Tallquist, MD;Teyton, L
通讯作者：
Teyton, L
影响因子：
15.9
作者：
Febbraio, M;Podrez, EA;Silverstein, RL
通讯作者：
Silverstein, RL
影响因子：
3.5
作者：
Ainge, Gary D.;Parlane, Natalie A.;Painter, Gavin F.
通讯作者：
Painter, Gavin F.
影响因子：
20.1
作者：
Bodart, V;Febbraio, M;Ong, H
通讯作者：
Ong, H