The Synergy between Palmitate and TNF-α for CCL2 Production Is Dependent on the TRIF/IRF3 Pathway: Implications for Metabolic Inflammation
The Synergy between Palmitate and TNF-α for CCL2 Production Is Dependent on the TRIF/IRF3 Pathway: Implications for Metabolic Inflammation
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DOI：
10.4049/jimmunol.1701552
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发表时间：
2018-05-15
影响因子：
4.4
通讯作者：
Rosen, Evan D.
中科院分区：
文献类型：
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作者：
Ahmad, Rasheed;Al-Roub, Areej;Rosen, Evan D.
趋化因子 CCL2（也称为 MCP-1）是单核细胞浸润脂肪组织的关键调节因子，在肥胖相关炎症和胰岛素抵抗的病理生理学中发挥着核心作用。目前尚不清楚肥胖人类和啮齿动物中 CCL2 的产生如何上调。由于据报道肥胖症中游离脂肪酸 (FFA) 棕榈酸酯和 TNF-α 水平升高，因此我们研究了这些药物是否相互作用以触发 CCL2 的产生。我们的数据表明，与单独处理相比，用棕榈酸酯和 TNF-α 处理 THP-1 和原代人单核细胞可导致 CCL2 产量显着增加。从机制上讲，我们发现棕榈酸酯和 TNF-a 协同生产 CCL2 不需要 MyD88，但通过阻断 TLR4 或 TRIF 会减弱它的作用。 IRF3 缺陷细胞没有表现出响应棕榈酸酯/TNF-α 的协同 CCL2 产生。此外，聚肌苷-聚胞苷酸激活IRF3可增强TNF-α诱导的CCL2分泌。有趣的是，棕榈酸/TNF-α 共刺激导致的 NF-κ B/AP-1 活性升高被 TRIF/IRF3 抑制减弱。饮食诱导的具有高 FFA 水平的 C57BL/6 肥胖小鼠显示血浆和脂肪组织中的 TNF-α 和 CCL2 之间存在很强的相关性，并且如预期的那样，与瘦小鼠相比，还显示脂肪组织巨噬细胞积累增加。在肥胖人群的脂肪组织样本中也观察到了类似的结果。总体而言，我们的研究结果支持这样一个模型：肥胖中 FFA 升高为 TNF-α 创造了一个环境，通过 TLR4/TRIF/IRF3 信号级联触发 CCL2 的产生，这代表了 FFA 对代谢炎症的潜在贡献。
The chemokine CCL2 (also known as MCP-1) is a key regulator of monocyte infiltration into adipose tissue, which plays a central role in the pathophysiology of obesity-associated inflammation and insulin resistance. It remains unclear how CCL2 production is upregulated in obese humans and rodents. Because elevated levels of the free fatty acid (FFA) palmitate and TNF-alpha have been reported in obesity, we studied whether these agents interact to trigger CCL2 production. Our data show that treatment of THP-1 and primary human monocytic cells with palmitate and TNF-alpha led to a marked increase in CCL2 production compared with either treatment alone. Mechanistically, we found that cooperative production of CCL2 by palmitate and TNF-a did not require MyD88, but it was attenuated by blocking TLR4 or TRIF. IRF3-deficient cells did not show synergistic CCL2 production in response to palmitate/TNF-alpha. Moreover, IRF3 activation by polyinosinic-polycytidylic acid augmented TNF-alpha-induced CCL2 secretion. Interestingly, elevated NF-kappa B/AP-1 activity resulting from palmitate/TNF-alpha costimulation was attenuated by TRIF/IRF3 inhibition. Diet-induced C57BL/6 obese mice with high FFAs levels showed a strong correlation between TNF-alpha and CCL2 in plasma and adipose tissue and, as expected, also showed increased adipose tissue macrophage accumulation compared with lean mice. Similar results were observed in the adipose tissue samples from obese humans. Overall, our findings support a model in which elevated FFAs in obesity create a milieu for TNF-alpha to trigger CCL2 production via the TLR4/TRIF/IRF3 signaling cascade, representing a potential contribution of FFAs to metabolic inflammation.