Zahoor Arshad, Yang Yaping, Yang Chao, Khan Sher Bahadar, Reix Christine, Anwar Farhan, Guo Meng-Yao, Deng Ganzhen
Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, People's Republic of China; College of Veterinary Science, 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.
Mol Immunol. 2020 Apr 2;122:1-12. doi: 10.1016/j.molimm.2020.03.007.
Mastitis is the most commonly diagnosed infectious disease reducing milk yield and quality and is accompanied by mammary tissue damage in both humans and animals. Mastitis incurs welfare and economic costs as well as environmental concerns regarding treatment. Staphylococcus aureus (S. aureus) is a prevalent Gram-positive bacteria and a major cause of mastitis, however, pathogenesis of the intrinsic anti-inflammatory response in mammary tissues is still principally unknown. Our aim, in combatting the S. aureus induced inflammatory response in mammary tissues, was to elucidate the intrinsic anti-inflammatory role of MerTK signaling. Here, we demonstrate that Mer receptor tyrosine kinase (MerTK) regulates an intrinsic negative feedback to balance the over-reaction of the host defense system. S. aureus elicits toll-like receptors 2 and 6 (TLR2/TLR6) signaling pathways, subsequently recruiting TRAF6, whose ubiquitination is intricate to the downstream signaling including MAPKs and NF-κB. We observed that TLR2/TLR6 activation, in response to S. aureus, was concomitant with induced MerTK activation, leading to raised expression of suppressor of cytokine signaling 1 and 3 (SOCS1, SOCS3) in wild type mice mammary tissues and epithelial cells. Meanwhile, S. aureus infection in MerTK mice showed significant increased phosphorylation of p65, IκBα, p38, JNK and ERK along with production of pro-inflammatory cytokines. Moreover, MerTK evidently inhibited S. aureus induced phosphorylation of STAT1 and subsequent SOCS1/SOCS3 expression which are pivotal in the negative feedback mechanism for targeting TRAF6 to inhibit the TLR2/TLR6 mediated immune response. Taken together, our findings demonstrate the importance of MerTK in the regulation of the intrinsic feedback during the inflammatory response induced by S. aureus through STAT1/SOCS1/SOCS3 in mice mammary tissues and mice mammary epithelial cells (MMECs).
乳腺炎是最常被诊断出的传染病，会降低产奶量和质量，在人类和动物中都会伴有乳腺组织损伤。乳腺炎会带来福利和经济成本，以及治疗方面的环境问题。金黄色葡萄球菌是一种常见的革兰氏阳性细菌，也是乳腺炎的主要病因，然而，乳腺组织中内在抗炎反应的发病机制仍主要不明。我们旨在对抗金黄色葡萄球菌诱导的乳腺组织炎症反应，以阐明MerTK信号传导的内在抗炎作用。在此，我们证明Mer受体酪氨酸激酶（MerTK）调节一种内在负反馈，以平衡宿主防御系统的过度反应。金黄色葡萄球菌引发Toll样受体2和6（TLR2/TLR6）信号通路，随后招募TRAF6，其泛素化对于包括丝裂原活化蛋白激酶（MAPKs）和核因子κB（NF-κB）在内的下游信号传导至关重要。我们观察到，响应金黄色葡萄球菌，TLR2/TLR6激活与诱导的MerTK激活同时发生，导致野生型小鼠乳腺组织和上皮细胞中细胞因子信号传导抑制因子1和3（SOCS1、SOCS3）的表达升高。同时，MerTK基因敲除小鼠中的金黄色葡萄球菌感染显示p65、IκBα、p38、JNK和ERK的磷酸化显著增加，以及促炎细胞因子的产生。此外，MerTK明显抑制金黄色葡萄球菌诱导的信号转导和转录激活因子1（STAT1）磷酸化以及随后的SOCS1/SOCS3表达，这在靶向TRAF6以抑制TLR2/TLR6介导的免疫反应的负反馈机制中至关重要。综上所述，我们的研究结果证明了MerTK在小鼠乳腺组织和小鼠乳腺上皮细胞（MMECs）中通过STAT1/SOCS1/SOCS3调节金黄色葡萄球菌诱导的炎症反应期间内在反馈的重要性。
