Academic Unit of Respiratory Medicine, Department of Infection and Immunity, University of Sheffield, Sheffield, UK.
J Leukoc Biol. 2011 Nov;90(5):855-65. doi: 10.1189/jlb.0211062. Epub 2011 May 11.
Novel therapeutics targeting neutrophilic inflammation are a major unmet clinical need in acute and chronic inflammation. The timely induction of neutrophil apoptosis is critical for inflammation resolution, and it is thought that acceleration of apoptosis may facilitate resolution at inflammatory sites. We previously demonstrated that a death receptor ligand, TRAIL, accelerates neutrophil apoptosis in vitro. We examined the role of TRAIL in neutrophil-dominant inflammation in WT and TRAIL-deficient mice. TRAIL deficiency did not alter constitutive neutrophil apoptosis, whereas exogenous TRAIL accelerated apoptosis of murine peripheral blood neutrophils. We compared TRAIL-deficient and WT mice in two independent models of neutrophilic inflammation: bacterial LPS-induced acute lung injury and zymosan-induced peritonitis. In both models, TRAIL-deficient mice had an enhanced inflammatory response with increased neutrophil numbers and reduced neutrophil apoptosis. Correction of TRAIL deficiency and supraphysiological TRAIL signaling using exogenous protein enhanced neutrophil apoptosis and reduced neutrophil numbers in both inflammatory models with no evidence of effects on other cell types. These data indicate the potential therapeutic benefit of TRAIL in neutrophilic inflammation.
针对中性粒细胞炎症的新型治疗方法是急性和慢性炎症的主要未满足的临床需求。及时诱导中性粒细胞凋亡对于炎症的解决至关重要，人们认为加速凋亡可能有助于炎症部位的解决。我们之前证明了一种死亡受体配体 TRAIL 可加速体外中性粒细胞凋亡。我们研究了 TRAIL 在 WT 和 TRAIL 缺陷小鼠中性粒细胞占优势的炎症中的作用。TRAIL 缺陷并不改变固有中性粒细胞凋亡，而外源性 TRAIL 加速了鼠外周血中性粒细胞的凋亡。我们在两种中性粒细胞炎症的独立模型中比较了 TRAIL 缺陷型和 WT 小鼠：细菌 LPS 诱导的急性肺损伤和酵母聚糖诱导的腹膜炎。在这两种模型中，TRAIL 缺陷型小鼠的炎症反应增强，中性粒细胞数量增加，中性粒细胞凋亡减少。用外源性蛋白纠正 TRAIL 缺陷和 TRAIL 信号的超生理水平增强了两种炎症模型中的中性粒细胞凋亡并减少了中性粒细胞数量，而没有证据表明对其他细胞类型有影响。这些数据表明 TRAIL 在中性粒细胞炎症中的潜在治疗益处。
