Oxidized Low-Density Lipoprotein Immune Complex Priming of the Nlrp3 Inflammasome Involves TLR and FcγR Cooperation and Is Dependent on CARD9.
Oxidized Low-Density Lipoprotein Immune Complex Priming of the Nlrp3 Inflammasome Involves TLR and FcγR Cooperation and Is Dependent on CARD9.
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DOI：
10.4049/jimmunol.1601563
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发表时间：
2017-03-01
期刊：
影响因子：
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通讯作者：
Major AS
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文献类型：
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作者：
Rhoads JP;Lukens JR;Wilhelm AJ;Moore JL;Mendez-Fernandez Y;Kanneganti TD;Major AS
氧化LDL （oxLDL）可以激活多种细胞的炎症反应，尤其是巨噬细胞和树突状细胞（dc）。有趣的是，循环中的大部分oxLDL与抗体结合，这些产生的免疫复合物（ic）是慢性炎症性疾病（如动脉粥样硬化、2型糖尿病、系统性红斑狼疮和类风湿性关节炎）的显著特征。oxldl - ic水平通常与疾病严重程度相关，过去的研究表明，oxldl - ic在巨噬细胞中引发了强有力的炎症反应。在这里，我们发现骨髓来源的树突状细胞（bmdc）与氧化低密度脂蛋白（oxLDL- ic）培养24小时后，与游离氧化低密度脂蛋白处理的bmdc相比，分泌更多的IL-1β，而TNFα和IL-6水平没有差异。用oxldl - ic治疗BMDCs可增加炎性小体相关基因Il1a、Il1b和Nlrp3的表达；用caspase 1抑制剂预处理可降低IL-1β的分泌。这种炎症体启动是由于oxLDL-IC通过多个受体信号传导，抑制CD36、TLR4和FcγR显著降低IL-1β分泌，以响应oxLDL-IC。通过这些受体发出的信号汇聚在接头蛋白CARD9上，CARD9是CARD9- bcl10 - malt1信号体复合物的一个组成部分，参与NF-κB易位。最后，氧化ldl - ic介导的IL-1β产生导致Th17极化和细胞因子分泌增加。总的来说，这些数据表明，与单独的oxLDL相比，oxLDL- ic通过一种独立且更强大的机制诱导炎症小体激活，并且这些ic可能在慢性疾病中具有免疫调节作用，而不仅仅是严重程度的生物标志物。
Oxidized LDL (oxLDL) is known to activate inflammatory responses in a variety of cells, especially macrophages and dendritic cells (DCs). Interestingly, much of the oxLDL in circulation is complexed to antibodies and these resulting immune complexes (ICs) are a prominent feature of chronic inflammatory disease such as atherosclerosis, Type-2 diabetes, systemic lupus erythematosus and rheumatoid arthritis. Levels of oxLDL-ICs often correlate with disease severity, and past studies have demonstrated that oxLDL-ICs elicit potent inflammatory responses in macrophages. Here we show that bone marrow-derived dendritic cells (BMDCs) incubated with oxLDL-ICs for 24 hrs secrete significantly more IL-1β compared to BMDCs treated with free oxLDL, while there was no difference in levels of TNFα or IL-6. Treatment of BMDCs with oxLDL-ICs increased expression of inflammasome-related genes Il1a, Il1b, and Nlrp3; and pre-treatment with a caspase 1 inhibitor decreased IL-1β secretion in response to oxLDL-ICs. This inflammasome priming was due to oxLDL-IC signaling via multiple receptors as inhibition of CD36, TLR4 and FcγR significantly decreased IL-1β secretion in response to oxLDL-ICs. Signaling through these receptors converged on the adaptor protein CARD9, a component of the CARD9-Bcl10-MALT1 signalosome complex involved in NF-κB translocation. Finally, oxLDL-IC-mediated IL-1β production resulted in increased Th17 polarization and cytokine secretion. Collectively, these data demonstrate that oxLDL-ICs induce inflammasome activation through a separate and more robust mechanism than oxLDL alone, and that these ICs may be immunomodulatory in chronic disease and not just biomarkers of severity.