Objective

Staphylococcus aureus (S. aureus), one of Gram-positive pathogen, is frequently associated with acute lung inflammation. The central feature of S. aureus acute lung inflammation are pulmonary dysfunctioning and impeded host defence response, which cause failure in inflammatory cytokines homeostasis and leads to serious tissue damage. However, the role of the Mer receptor tyrosine kinase (MerTK) in the lung following S. aureus infection remains elusive. Here, we investigate whether MerTK alleviates S. aureus induced uncontrolled inflammation through negatively regulating toll-like receptor 2 and 6 (TLR2/ TLR6) via suppressor of cytokine signalling 1, 3 (SOCS1/SOCS3).

Methods and results

We found in mice lung tissues and RAW 264.7 macrophages upon S. aureus infection activates TLR2 and TLR6 driven mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB) signalling pathways, resulting in production of inflammatory cytokines including tumour necrosis factor-α (TNF-α), interleukin 1β (IL-1β), interleukin 6 (IL-6). Furthermore, S. aureus-infection groups showed a significant up-regulation of MerTK which serves as mediator of SOCS1 and SOCS3. Subsequently, through feedback mechanism SOCS1/3 degrade Mal, resulting in inhibition of downstream TLR mediated inflammatory pathways. Moreover, MerTK^−/− mice lung tissues and silencing MerTK in RAW 264.7 inhibited the S. aureus-induced activation of MerTK, which significantly upregulated the phosphorylation of crucial protein in MAPKs (ERK, JNK, p38) and NF-κB (IĸBα, p65) signalling pathways, as well as the production of pro-inflammatory cytokines.

Conclusion

Collectively, these findings indicate the important role of MerTK in self-regulatory resolution of S. aureus-induced inflammatory pathways and cytokines through intrinsic SOCS1 and SOCS3 repressed feedback on TLR2, TLR6 both in vivo and in vitro.

中文翻译：

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MerTK 通过 SOCS1/SOCS3 和 Mal 负调节金黄色葡萄球菌诱导的炎症反应。

客观的

金黄色葡萄球菌( S. aureus ) 是一种革兰氏阳性病原体，常与急性肺部炎症有关。金黄色葡萄球菌急性肺部炎症的核心特征是肺功能障碍和宿主防御反应受阻，导致炎性细胞因子稳态失灵并导致严重的组织损伤。然而，Mer 受体酪氨酸激酶 (MerTK) 在金黄色葡萄球菌感染后肺中的作用仍然难以捉摸。在这里，我们研究了 MerTK 是否通过抑制细胞因子信号传导 1、3 (SOCS1/SOCS3)负调节 Toll 样受体 2 和 6 (TLR2/TLR6)来缓解金黄色葡萄球菌诱导的不受控制的炎症。

方法和结果

我们在金黄色葡萄球菌感染后的小鼠肺组织和 RAW 264.7 巨噬细胞中发现激活 TLR2 和 TLR6 驱动的丝裂原活化蛋白激酶 (MAPK) 和核因子κB (NF-κB) 信号通路，导致产生炎性细胞因子，包括肿瘤坏死因子-α (TNF-α)、白介素 1β (IL-1β)、白介素 6 (IL-6)。此外，金黄色葡萄球菌感染组显示出作为 SOCS1 和 SOCS3 介质的 MerTK 的显着上调。随后，SOCS1/3 通过反馈机制降解 Mal，从而抑制下游 TLR 介导的炎症通路。此外，MerTK ^-/-小鼠肺组织和沉默 RAW 264.7 中的MerTK抑制了金黄色葡萄球菌-诱导 MerTK 的激活，显着上调 MAPK（ERK、JNK、p38）和 NF-κB（IĸBα、p65）信号通路中关键蛋白的磷酸化，以及促炎细胞因子的产生。

结论

总的来说，这些发现表明，MerTK在体内和体外通过对 TLR2、TLR6 的内在 SOCS1 和 SOCS3 抑制反馈在金黄色葡萄球菌诱导的炎症通路和细胞因子的自我调节解决中发挥重要作用。