Bimodal role of NADPH oxidases in the regulation of biglycan-triggered IL-1β synthesis.
Bimodal role of NADPH oxidases in the regulation of biglycan-triggered IL-1β synthesis.
复制标题
DOI：
10.1016/j.matbio.2015.12.005
复制
发表时间：
2016-01
期刊：
影响因子：
--
通讯作者：
Schaefer L
中科院分区：
文献类型：
--
作者：
Hsieh LT;Frey H;Nastase MV;Tredup C;Hoffmann A;Poluzzi C;Zeng-Brouwers J;Manon-Jensen T;Schröder K;Brandes RP;Iozzo RV;Schaefer L
双糖链蛋白聚糖是一种普遍存在的蛋白聚糖，当从细胞外基质中释放时可作为一种危险信号。因此，双糖链蛋白聚糖以依赖 toll样受体2（TLR2）、toll样受体4（TLR4）和活性氧物质（ROS）的方式触发白细胞介素 - 1β（IL - 1β）的合成和成熟。在此，我们发现双糖链蛋白聚糖在体外和体内通过不同的TLR途径调节NADPH氧化酶（NOX）1、2和4酶的表达、活性和稳定性，从而自主调节IL - 1β产生的平衡。在原代小鼠巨噬细胞中，双糖链蛋白聚糖触发NOX1/4介导的ROS产生，从而增强IL - 1β的表达。令人惊讶的是，双糖链蛋白聚糖通过与TLR4选择性相互作用，因增强NOX2的合成和激活而抑制IL - 1β。NOX2的合成是由包含Toll/IL - 1R结构域的衔接分子诱导干扰素 - β（TRIF）介导的。通过髓样分化初级反应蛋白（MyD88）以及Rac1激活和Erk磷酸化，双糖链蛋白聚糖触发细胞质NOX2亚基p47phox向质膜的转位，这是NOX2激活的必要步骤。相反，通过结合TLR2，可溶性双糖链蛋白聚糖刺激热休克蛋白（HSP）70的表达，HSP70与NOX2结合，从而削弱NOX2对IL - 1β表达的抑制功能。值得注意的是，缺乏双糖链蛋白聚糖的遗传背景降低了HSP70的表达，挽救了Nox2 - /y小鼠在肾缺血再灌注损伤模型中肾脏IL - 1β产生的增强，并改善了肾功能。在此，我们提供了一种新的机制，即危险分子双糖链蛋白聚糖通过不同的TLR途径影响NOX2的合成和激活，从而调节炎症的严重程度。因此，选择性抑制双糖链蛋白聚糖 - TLR2或双糖链蛋白聚糖 - TLR4信号传导可能是治疗ROS介导的炎症性疾病的一种新的治疗方法。
Biglycan, a ubiquitous proteoglycan, acts as a danger signal when released from the extracellular matrix. As such, biglycan triggers the synthesis and maturation of interleukin-1β (IL-1β) in a Toll-like receptor (TLR) 2-, TLR4-, and reactive oxygen species (ROS)-dependent manner. Here, we discovered that biglycan autonomously regulates the balance in IL-1β production in vitro and in vivo by modulating expression, activity and stability of NADPH oxidase (NOX) 1, 2 and 4 enzymes via different TLR pathways. In primary murine macrophages, biglycan triggered NOX1/4-mediated ROS generation, thereby enhancing IL-1β expression. Surprisingly, biglycan inhibited IL-1β due to enhancement of NOX2 synthesis and activation, by selectively interacting with TLR4. Synthesis of NOX2 was mediated by adaptor molecule Toll/IL-1R domain-containing adaptor inducing IFN-β (TRIF). Via myeloid differentiation primary response protein (MyD88) as well as Rac1 activation and Erk phosphorylation, biglycan triggered translocation of the cytosolic NOX2 subunit p47phox to the plasma membrane, an obligatory step for NOX2 activation. In contrast, by engaging TLR2, soluble biglycan stimulated the expression of heat shock protein (HSP) 70, which bound to NOX2, and consequently impaired the inhibitory function of NOX2 on IL-1β expression. Notably, a genetic background lacking biglycan reduced HSP70 expression, rescued the enhanced renal IL-1β production and improved kidney function of Nox2−/y mice in a model of renal ischemia reperfusion injury. Here, we provide a novel mechanism where the danger molecule biglycan influences NOX2 synthesis and activation via different TLR pathways, thereby regulating inflammation severity. Thus, selective inhibition of biglycan-TLR2 or biglycan-TLR4 signaling could be a novel therapeutic approach in ROS-mediated inflammatory diseases.
登录
查看更多内容
影响因子：
4
作者：
Gianni, Davide;Taulet, Nicolas;Zhang, Hui;DerMardirossian, Celine;Kister, Jeremy;Martinez, Luis;Roush, William R.;Brown, Steven J.;Bokoch, Gary M.;Rosen, Hugh
通讯作者：
Rosen, Hugh
影响因子：
6.9
作者：
Berendsen, Agnes D.;Pinnow, Emily L.;Maeda, Azusa;Brown, Aaron C.;McCartney-Francis, Nancy;Kram, Vardit;Owens, Rick T.;Robey, Pamela G.;Holmbeck, Kenn;de Castro, Luis F.;Kilts, Tina M.;Young, Marian F.
通讯作者：
Young, Marian F.
影响因子：
6.2
作者：
Chen, XD;Shi, ST;Young, MF
通讯作者：
Young, MF
影响因子：
4.8
作者：
Ambasta, RK;Kumar, P;Brandes, RP
通讯作者：
Brandes, RP
影响因子：
13.5
作者：
Aoyama, Tomonori;Paik, Yong-Han;Watanabe, Sumio;Laleu, Benoit;Gaggini, Francesca;Fioraso-Cartier, Laetitia;Molango, Sophie;Heitz, Freddy;Merlot, Cedric;Szyndralewiez, Cedric;Page, Patrick;Brenner, David A.
通讯作者：
Brenner, David A.