Baranova Irina N, Bocharov Alexander V, Vishnyakova Tatyana G, Chen Zhigang, Ke Yunbo, Birukova Anna A, Yuen Peter S T, Tsuji Takayuki, Star Robert A, Birukov Konstantin G, Patterson Amy P, Eggerman Thomas L
Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Cells. 2024 Dec 3;13(23):1992. doi: 10.3390/cells13231992.
The class B scavenger receptor CD36 is known to bind and mediate the transport of lipid-related ligands and it functions as a pattern recognition receptor (PRR) for a variety of pathogens, including bacteria and viruses. In this study, we assessed CD36's role as a PRR mediating pro-inflammatory effects of several known Danger-Associated Molecular Patterns (DAMPs) used either as a single preparation or as a combination of DAMPs in the form of total cell/skeletal muscle tissue lysates. Our data demonstrated that multiple DAMPs, including HMGB1, HSPs, histone H3, SAA, and oxPAPC, as well as cell/tissue lysate preparations, induced substantially higher (7-10-fold) IL-8 cytokine responses in HEK293 cells overexpressing CD36 compared to control WT cells. At the same time, DAMP-induced secretion of IL-6 in bone marrow-derived macrophages (BMDM) from CD36-/- mice was markedly (2-3 times) reduced, as compared to macrophages from normal mice. Synthetic amphipathic helical peptides (SAHPs), known CD36 ligands, efficiently blocked CD36-dependent inflammatory responses induced by both cell and tissue lysates, HMGB1 and histone H3 in CD36+ cells. IP injection of total cellular lysate preparation induced inflammatory responses that were assessed by the expression of liver and lung pro-inflammatory markers, including IL-6, TNF-α, CD68, and CXCL1, and was reduced by ~50% in CD36-deficient mice compared to normal mice. Our findings demonstrate that CD36 is a PRR contributing to the innate immune response via mediating DAMP-induced inflammatory signaling and highlight the importance of this receptor as a potential therapeutic target in DAMP-associated inflammatory conditions.
已知B类清道夫受体CD36可结合并介导脂质相关配体的转运，它作为多种病原体（包括细菌和病毒）的模式识别受体（PRR）发挥作用。在本研究中，我们评估了CD36作为PRR的作用，该PRR介导几种已知的危险相关分子模式（DAMP）的促炎作用，这些DAMP既可以单独使用，也可以以全细胞/骨骼肌组织裂解物的形式组合使用。我们的数据表明，与对照野生型细胞相比，包括HMGB1、热休克蛋白（HSPs）、组蛋白H3、血清淀粉样蛋白A（SAA）和氧化型磷脂酰胆碱（oxPAPC）在内的多种DAMP以及细胞/组织裂解物制剂，在过表达CD36的HEK293细胞中诱导的白细胞介素-8（IL-8）细胞因子反应显著更高（约7至10倍）。同时，与正常小鼠的巨噬细胞相比，来自CD36基因敲除小鼠的骨髓来源巨噬细胞（BMDM）中DAMP诱导的IL-6分泌明显减少（约2至3倍）。合成两亲性螺旋肽（SAHP）是已知的CD36配体，可有效阻断CD36 +细胞中由细胞和组织裂解物、HMGB1和组蛋白H3诱导的CD36依赖性炎症反应。腹腔注射全细胞裂解物制剂诱导的炎症反应通过肝脏和肺脏促炎标志物（包括IL-6、肿瘤坏死因子-α（TNF-α）、CD68和CXC趋化因子配体1（CXCL1））的表达进行评估，与正常小鼠相比，CD36缺陷小鼠中的炎症反应降低了约50％。我们的研究结果表明，CD36是一种PRR，通过介导DAMP诱导的炎症信号传导促进先天免疫反应，并突出了该受体作为DAMP相关炎症病症潜在治疗靶点的重要性。
