CD36 Is Essential for Regulation of the Host Innate Response to Staphylococcus aureus α-Toxin-Mediated Dermonecrosis.
CD36 Is Essential for Regulation of the Host Innate Response to Staphylococcus aureus α-Toxin-Mediated Dermonecrosis.
复制标题
DOI：
10.4049/jimmunol.1500500
复制
发表时间：
2015-09-01
期刊：
影响因子：
--
通讯作者：
Hall PR
中科院分区：
文献类型：
--
作者：
Castleman MJ;Febbraio M;Hall PR
金黄色葡萄球菌是美国皮肤和皮肤结构感染(SSSI)的主要原因。甲型溶血素(Hla)是金黄色葡萄球菌分泌的一种致孔毒素，是导致组织坏死的主要因素，它促使对宿主防御金黄色葡萄球菌感染至关重要的中性粒细胞的招募。然而，未能清除凋亡的中性粒细胞会对宿主组织造成损害，这表明中性粒细胞清除机制对于限制人类白细胞抗原介导的皮损是必不可少的。我们推测，CD36是一种清道夫受体，可以促进细胞的识别，在金黄色葡萄球菌SSSI过程中，CD36将在调节人类白细胞抗原(HL A)介导的炎症和组织损伤中发挥重要作用。在这里，我们显示巨噬细胞上的CD36负向调节由产生人类白细胞抗原的金黄色葡萄球菌引起的皮损。这一调节与细菌负荷无关，因为CD36还可以限制无菌细菌上清液或纯化的人类白细胞抗原(Hla)中毒引起的皮损。与CD36+/+(野生型)小鼠相比，CD36+/+−/−小鼠上清液中毒性皮损明显增大，中性粒细胞聚集增加，IL-1β表达增加。CD36−/−小鼠的中性粒细胞耗尽可以阻止这种表型，证明了中性粒细胞在该模型中对组织损伤的贡献。此外，给中毒部位附近的巨噬细胞注射CD36+/+，而不是CD36−/−，可以减少皮损、IL-1β的产生和中性粒细胞的聚集，达到野生型小鼠的水平。这种治疗作用通过抑制CD36+/+巨噬细胞中的肌动蛋白聚合而逆转，从而支持一种作用机制，即CD36依赖的巨噬细胞吞噬凋亡的中性粒细胞调节人类白细胞抗原介导的皮损。综上所述，这些数据表明，CD36对于控制宿主对金黄色葡萄球菌皮肤感染的先天反应是必不可少的。
Staphylococcus aureus is the primary cause of skin and skin structure infections (SSSI) in the USA. Alpha-hemolysin (Hla), a pore-forming toxin secreted by S. aureus and a major contributor to tissue necrosis, prompts recruitment of neutrophils critical for host defense against S. aureus infections. However, the failure to clear apoptotic neutrophils can result in damage to host tissues, suggesting that mechanisms of neutrophil clearance are essential to limiting Hla-mediated dermonecrosis. We hypothesized that CD36, a scavenger receptor which facilitates recognition of apoptosing cells, would play a significant role in regulating Hla-mediated inflammation and tissue injury during S. aureus SSSI. Here we show that CD36 on macrophages negatively regulates dermonecrosis caused by Hla-producing S. aureus. This regulation is independent of bacterial burden, as CD36 also limits dermonecrosis caused by intoxication with sterile bacterial supernatant or purified Hla. Dermonecrotic lesions of supernatant intoxicated CD36−/− mice are significantly larger, with increased neutrophil accumulation and IL-1β expression, compared to CD36+/+ (wild-type) mice. Neutrophil depletion of CD36−/− mice prevents this phenotype, demonstrating the contribution of neutrophils to tissue injury in this model. Furthermore, administration of CD36+/+, but not CD36−/−, macrophages near the site of intoxication reduces dermonecrosis, IL-1β production and neutrophil accumulation to levels seen in wild-type mice. This therapeutic effect is reversed by inhibiting actin polymerization in the CD36+/+ macrophages, supporting a mechanism of action whereby CD36-dependent macrophage phagocytosis of apoptotic neutrophils regulates Hla-mediated dermonecrosis. Together, these data demonstrate that CD36 is essential for controlling the host innate response to S. aureus skin infection.