Department of Biomedicine, Division of Infection Biology, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland.
Immunol Lett. 2011 Mar 30;135(1-2):17-23. doi: 10.1016/j.imlet.2010.09.007. Epub 2010 Sep 25.
Toll-like receptors play an essential role in the detection of invading pathogens. TLR2 is expressed in high concentrations on neutrophils and has been implicated as a critical mediator inducing host antimicrobial defenses against Gram-positive bacteria. Neutrophil responses induced via TLR2 are likely to have important clinical consequences, since Gram-positive organisms, such as Staphylococcus aureus, are an increasingly important source of severe infections. In the present study, we report that TLR2 has a central role in killing of S. aureus by murine PMN via enhancement of NADPH oxidase activity. PMN from TLR2-deficient mice showed a similar inability to kill S. aureus in vitro and under in vivo-like conditions as PMN with a non-functional NADPH oxidase. This defect in killing by TLR2-deficient PMN was not related to phagocytosis but caused by delayed and reduced NADPH oxidase-mediated production of superoxide anion in response to S. aureus and other Gram-positive bacteria. The cause of this was independent of PI3K- and p38 signaling. The TLR2-enhanced induction of superoxide was a defect in proper NADPH oxidase assembly. We hypothesize that early activation of TLR2-signaling may enhance p47(phox) phosphorylation subsequent to phagocytosis-mediated phosphorylation. Summarized, these data demonstrate a novel role of TLR2 in the killing of S. aureus by ensuring a rapid activation of the NADPH oxidase complex.
Toll 样受体在检测入侵病原体方面发挥着重要作用。TLR2 在中性粒细胞中高浓度表达，并被认为是诱导宿主针对革兰氏阳性菌产生抗微生物防御的关键介质。通过 TLR2 诱导的中性粒细胞反应可能具有重要的临床后果，因为革兰氏阳性菌，如金黄色葡萄球菌，是严重感染的日益重要的来源。在本研究中，我们报告 TLR2 通过增强 NADPH 氧化酶活性在金黄色葡萄球菌被鼠 PMN 杀伤中起核心作用。TLR2 缺陷型 PMN 表现出类似于无功能 NADPH 氧化酶的 PMN 在体外和类似于体内的条件下不能杀伤金黄色葡萄球菌的类似能力。TLR2 缺陷型 PMN 杀伤能力的这种缺陷与吞噬作用无关，但由于对金黄色葡萄球菌和其他革兰氏阳性菌的 NADPH 氧化酶介导的超氧阴离子产生的延迟和减少而导致。这种缺陷的原因与 PI3K 和 p38 信号无关。TLR2 增强的超氧化物诱导是 NADPH 氧化酶组装不当的缺陷。我们假设 TLR2 信号的早期激活可能会增强吞噬作用介导的磷酸化之后的 p47(phox)磷酸化。总之，这些数据表明 TLR2 在金黄色葡萄球菌杀伤中的新作用是通过确保 NADPH 氧化酶复合物的快速激活来实现的。
