Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, People's Republic of China; College of Veterinary Sciences, The University of Agriculture Peshawar, Pakistan.
Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, People's Republic of China.
Immunobiology. 2020 Jul;225(4):151960. doi: 10.1016/j.imbio.2020.151960. Epub 2020 May 21.
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).
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.
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.
金黄色葡萄球菌（S. aureus）是革兰氏阳性病原体之一，常与急性肺炎症有关。S. aureus 急性肺炎症的中心特征是肺功能障碍和宿主防御反应受阻，导致炎症细胞因子动态平衡失调，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的肺部中的作用仍不清楚。在这里，我们研究了 MerTK 是否通过抑制细胞因子信号转导 1、3（SOCS1/SOCS3）来负调控 Toll 样受体 2 和 6（TLR2/TLR6），从而减轻金黄色葡萄球菌诱导的失控性炎症。
我们发现，在金黄色葡萄球菌感染的小鼠肺组织和 RAW 264.7 巨噬细胞中，TLR2 和 TLR6 驱动的丝裂原活化蛋白激酶（MAPKs）和核因子 kappa B（NF-κB）信号通路被激活，导致肿瘤坏死因子-α（TNF-α）、白细胞介素 1β（IL-1β）、白细胞介素 6（IL-6）等炎症细胞因子的产生。此外，金黄色葡萄球菌感染组中 MerTK 的表达显著上调，MerTK 作为 SOCS1 和 SOCS3 的介质。随后，通过反馈机制，SOCS1/3 降解 Mal，从而抑制下游 TLR 介导的炎症途径。此外，MerTK 敲除小鼠肺组织和沉默 RAW 264.7 中的 MerTK 抑制了金黄色葡萄球菌诱导的 MerTK 激活，这显著上调了 MAPKs（ERK、JNK、p38）和 NF-κB（IĸBα、p65）信号通路中的关键蛋白的磷酸化以及促炎细胞因子的产生。
总之，这些发现表明，MerTK 通过内在的 SOCS1 和 SOCS3 对 TLR2 和 TLR6 的抑制性反馈，在体内和体外均在金黄色葡萄球菌诱导的炎症途径和细胞因子的自我调节性消退中发挥重要作用。
