PCSK9 induces a pro-inflammatory response in macrophages.
PCSK9 induces a pro-inflammatory response in macrophages.
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DOI：
10.1038/s41598-018-20425-x
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发表时间：
2018-02-02
影响因子：
4.6
通讯作者：
Ferri N
中科院分区：
文献类型：
--
作者：
Ricci C;Ruscica M;Camera M;Rossetti L;Macchi C;Colciago A;Zanotti I;Lupo MG;Adorni MP;Cicero AFG;Fogacci F;Corsini A;Ferri N
斑块内巨噬细胞释放的炎性细胞因子通过诱导中膜平滑肌细胞（SMC）的增殖和迁移参与动脉粥样硬化形成。PCSK 9存在于动脉粥样硬化斑块内并由SMC释放，但其功能仍不清楚。在本研究中，我们测试了PCSK 9可以引起对巨噬细胞的促炎作用的假设。将THP-1衍生的巨噬细胞和人原代巨噬细胞暴露于不同浓度（0.250 μg/ml至2.5 μg/ml）的人重组PCSK 9（hPCSK 9）。与2.5 µg/ml PCSK 9孵育24 h后，在两种细胞类型中均观察到IL-1β、IL-6、TNF-α、CXCL 2和MCP 1 mRNA的显著诱导。THP-1巨噬细胞与过表达hPCSK 9的HepG 2共培养，巨噬细胞中TNF-α和IL-1β mRNA的表达量分别增加了2.4 ± 0.5倍和8.6 ± 1.8倍。与野生型BMM相比，hPCSK 9对小鼠LDLR−/−骨髓巨噬细胞（BMM）中TNF-α mRNA的影响显著受损（LDLR−/−和LDLR+/+分别为4.3 ± 1.6倍和31.1 ± 6.1倍）。最后，观察到健康成人受试者（男性533例，女性537例）的PCSK 9和TNF-α血浆水平呈正相关（B = 8.73，95%CI 7.54 - 9.93，p < 0.001）。总之，本研究提供了PCSK 9对巨噬细胞的促炎作用的证据，主要依赖于LDLR。
Intraplaque release of inflammatory cytokines from macrophages is implicated in atherogenesis by inducing the proliferation and migration of media smooth muscle cells (SMCs). PCSK9 is present and released by SMCs within the atherosclerotic plaque but its function is still unknown. In the present study, we tested the hypothesis that PCSK9 could elicit a pro-inflammatory effect on macrophages. THP-1-derived macrophages and human primary macrophages were exposed to different concentrations (0.250 ÷ 2.5 µg/ml) of human recombinant PCSK9 (hPCSK9). After 24 h incubation with 2.5 µg/ml PCSK9, a significant induction of IL-1β, IL-6, TNF-α, CXCL2, and MCP1 mRNA, were observed in both cell types. Co-culture of THP-1 macrophages with HepG2 overexpressing hPCSK9 also showed the induction of TNF-α (2.4 ± 0.5 fold) and IL-1β (8.6 ± 1.8 fold) mRNA in macrophages. The effect of hPCSK9 on TNF-α mRNA in murine LDLR−/− bone marrow macrophages (BMM) was significantly impaired as compared to wild-type BMM (4.3 ± 1.6 fold vs 31.1 ± 6.1 fold for LDLR−/− and LDLR+/+, respectively). Finally, a positive correlation between PCSK9 and TNF-α plasma levels of healthy adult subjects (males 533, females 537) was observed (B = 8.73, 95%CI 7.54 ÷ 9.93, p < 0.001). Taken together, the present study provides evidence of a pro-inflammatory action of PCSK9 on macrophages, mainly dependent by the LDLR.
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影响因子：
5.3
作者：
Ferri, Nicola;Tibolla, Gianpaolo;Catapano, Alberico Luigi
通讯作者：
Catapano, Alberico Luigi
影响因子：
3.7
作者：
Canuel M;Sun X;Asselin MC;Paramithiotis E;Prat A;Seidah NG
通讯作者：
Seidah NG
PCSK9 在涉及 TLR4/NF-κ B 通路的动脉粥样硬化炎症促进中的新作用
影响因子：
5.3
作者：
Tang, Zhi-Han;Peng, Juan;Jiang, Zhi-Sheng
通讯作者：
Jiang, Zhi-Sheng
DOI：
10.1002/path.4630
发表时间：
2016-01
期刊：
The Journal of pathology
影响因子：
--
作者：
Giunzioni I;Tavori H;Covarrubias R;Major AS;Ding L;Zhang Y;DeVay RM;Hong L;Fan D;Predazzi IM;Rashid S;Linton MF;Fazio S
通讯作者：
Fazio S
影响因子：
11.1
作者：
Hansson GK;Libby P;Tabas I
通讯作者：
Tabas I