K63-Linked Polyubiquitination on TRAF6 Regulates LPS-Mediated MAPK Activation, Cytokine Production, and Bacterial Clearance in Toll-Like Receptor 7/8 Primed Murine Macrophages.
K63-Linked Polyubiquitination on TRAF6 Regulates LPS-Mediated MAPK Activation, Cytokine Production, and Bacterial Clearance in Toll-Like Receptor 7/8 Primed Murine Macrophages.
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DOI：
10.3389/fimmu.2018.00279
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发表时间：
2018
影响因子：
7.3
通讯作者：
Samavati L
中科院分区：
文献类型：
--
作者：
Talreja J;Samavati L
病毒感染后细菌性肺炎是与季节性和大流行性流感病毒疾病相关的发病和死亡的主要原因。尽管近年来人们在发现病毒-细菌感染后及其并发症的机制方面付出了很多努力，但对细菌感染易感性增加的分子机制仍然知之甚少。在这项研究中，我们重点关注调节小鼠巨噬细胞免疫反应的途径，并通过用 Toll 样受体 (TLR) 7/8 配体 (R848) 预处理骨髓源性巨噬细胞 (BMDM) 并随后用 TLR2/4 激动剂激发来模拟细菌感染，从而模拟病毒后细菌感染。我们发现 R848 引发的 BMDM 在随后暴露于 TLR2/4 配体后会产生炎症细胞因子生成增强的反应，尤其是 IL-6 和 TNF-α。 R848 引发的 BMDM 中响应 TLR2/4 的细胞因子产生增强是由于 TGF-β 激活激酶 (TAK) 1 磷酸化增加以及随后 ERK 和 p38 MAPK 的激活。此外，我们发现 R848 引发导致 TRAF6 上 K63 连接的多聚泛素化增加。 TRAF6 上的 K63 连接的多聚泛素化是导致包括 TAK1 在内的下游途径增强激活的信号。重要的是，感染活细菌的 R848 引发的 BMDM 表现出细菌清除率降低。雷帕霉素 3 的小分子增强剂是一种泛素连接酶抑制剂，可逆转 R848 引发的 BMDM 中 TRAF6 上 K63 连接的多泛素化，随后降低 TAK1 和 MAPK 磷酸化以及细胞因子的产生，并逆转 BMDM 降低的细菌清除能力。我们的研究可能提供一个新的分子靶点来缓解病毒-细菌感染后的感染。
Post viral infection bacterial pneumonia is a major cause of morbidity and mortality associated with both seasonal and pandemic influenza virus illness. Despite much efforts put into the discovery of mechanisms of post viral–bacterial infections and their complications in recent years, the molecular mechanisms underlying the increased susceptibility to bacterial infection remain poorly understood. In this study, we focused on the pathways regulating immune responses in murine macrophages and modeled post viral–bacterial infections through pretreatment of bone marrow-derived macrophages (BMDMs) with a toll-like receptor (TLR) 7/8 ligand (R848) and subsequent challenge with TLR2/4 agonists to mimic bacterial infection. We found R848-primed BMDMs upon subsequent exposure to TLR2/4 ligands respond with enhanced inflammatory cytokine production, especially IL-6 and TNF-α. The enhanced cytokine production in R848-primed BMDMs in response to TLR2/4 was due to increased TGF-β-activated kinase (TAK) 1 phosphorylation with subsequent activation of ERK and p38 MAPKs. Furthermore, we identified that R848 priming leads to increased K63-linked polyubiquitination on TRAF6. K63-linked polyubiquitination on TRAF6 is a signal leading to enhanced activation of downstream pathways including TAK1. Importantly, R848-primed BMDMs infected with live bacteria exhibited decreased bacterial clearance. Small-molecule enhancer of rapamycin 3, an ubiquitin ligase inhibitor reversed the K63-linked polyubiquitination on TRAF6 in R848-primed BMDMs and subsequently decreased TAK1 and MAPK phosphorylation, and cytokine production as well as reversed the decreased bacterial clearance capacity of BMDMs. Our study may provide a novel molecular target to alleviate post viral–bacterial infections.
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DOI：
10.4049/jimmunol.0804343
发表时间：
2009-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Frazier WJ;Wang X;Wancket LM;Li XA;Meng X;Nelin LD;Cato AC;Liu Y
通讯作者：
Liu Y
影响因子：
46.9
作者：
通讯作者：
--
影响因子：
3.7
作者：
Julian MW;Strange HR;Ballinger MN;Hotchkiss RS;Papenfuss TL;Crouser ED
通讯作者：
Crouser ED
影响因子：
15.3
作者：
Didierlaurent, Arnaud;Goulding, John;Patel, Seema;Snelgrove, Robert;Low, Lionel;Bebien, Magali;Lawrence, Toby;van Rijt, Leonie S.;Lambrecht, Bart N.;Sirard, Jean-Claude;Hussell, Tracy
通讯作者：
Hussell, Tracy
影响因子：
4.4
作者：
Bagchi, Aranya;Herrup, Elizabeth A.;Hellman, Judith
通讯作者：
Hellman, Judith