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).

中文翻译：

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MerTK通过Toll样受体信号传导在乳腺中负调控金黄色葡萄球菌诱导的炎症反应。

乳腺炎是最常见的感染性疾病，会降低牛奶的产量和质量，并伴有人类和动物的乳腺组织损伤。乳腺炎招致福利和经济成本以及有关治疗的环境问题。金黄色葡萄球菌（S. aureus）是革兰氏阳性细菌的普遍存在，是乳腺炎的主要原因，但是，乳腺组织内在抗炎反应的发病机理仍是主要未知的。我们在对抗金黄色葡萄球菌诱导的乳腺组织炎症反应中的目的是阐明MerTK信号传导的内在抗炎作用。在这里，我们证明Mer受体酪氨酸激酶（MerTK）调节内在的负反馈，以平衡宿主防御系统的过度反应。S. 金黄色葡萄球菌会引发toll样受体2和6（TLR2 / TLR6）信号通路，随后募集TRAF6，其泛素化与包括MAPK和NF-κB在内的下游信号复杂。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1和3（SOCS1，SOCS3）抑制剂的表达升高。同时，MerTK-/-小鼠中的金黄色葡萄球菌感染显示p65，IκBα，p38，JNK和ERK的磷酸化显着增加，并产生促炎性细胞因子。此外，MerTK-/-明显抑制了S。金黄色葡萄球菌引起的STAT1磷酸化和随后的SOCS1 / SOCS3表达，这在靶向TRAF6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，我们的发现证明了在小鼠乳腺组织和小鼠乳腺上皮细胞（MMEC）中，MerTK在金黄色葡萄球菌通过STAT1 / SOCS1 / SOCS3引起的炎症反应中调节内在反馈的重要性。