Serum Amyloid A Promotes Lung Neutrophilia by Increasing IL-17A Levels in the Mucosa and γδ T Cells
Serum Amyloid A Promotes Lung Neutrophilia by Increasing IL-17A Levels in the Mucosa and γδ T Cells
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DOI：
10.1164/rccm.201211-2139oc
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发表时间：
2013-07-15
影响因子：
24.7
通讯作者：
Bozinovski, Steven
中科院分区：
文献类型：
--
作者：
Anthony, Desiree;Seow, Huei Jiunn;Bozinovski, Steven
理论基础：中性粒细胞炎症是慢性阻塞性肺疾病(COPD)和COPD感染性加重的重要病理特征。血清淀粉样蛋白A(SAA)通过与肺粘膜ALX/FPR2受体相互作用促进中性粒细胞炎症。目的：探讨SAA是否通过IL-17A依赖的机制引起中性粒细胞炎症。方法：在COPD患者肺切片和SAA慢性暴露小鼠模型上，研究SAA与中性粒细胞的关系。用抗IL-17A的中和抗体阻断体内SAA反应，用细胞分选策略确定细胞来源。测量和主要结果：COPD患者SAA mRNA表达与组织中性粒细胞呈正相关(P<；0.05)。SAA主要促进T(H)17极化细胞因子IL-6的表达，而15-表脂蛋白A(4)和ALX/FPR2配体则相反。体内IL-17A中和抗体可显著减轻SAA诱导的炎症反应。SAA诱导的IL-17A的细胞来源包括CD4(+)T细胞、Gamma Delta T细胞和富含上皮细胞的Epcam(+)CD45(-)群体。结论：SAA-IL-17A轴是COPD患者持续中性粒细胞炎症的重要天然防御网络，通过调节ALX/FPR2受体可以靶向IL-17A介导的肺免疫功能异常。
Rationale: Neutrophilic inflammation is an important pathologic feature of chronic obstructive pulmonary disease (COPD) and infectious exacerbations of COPD. Serum amyloid A (SAA) promotes neutrophilic inflammation by its interaction with lung mucosal ALX/FPR2 receptors. However, little is known about how this endogenous mediator regulates IL-17A immunity.Objectives: To determine whether SAA causes neutrophilic inflammation by IL-17A-dependent mechanisms.Methods: The relationship between SAA and neutrophils was investigated in lung sections from patients with COPD and a chronic mouse model of SAA exposure. A neutralizing antibody to IL-17A was used to block SAA responses in vivo, and a cell-sorting strategy was used to identify cellular sources.Measurements and Main Results: SAA mRNA expression was positively associated with tissue neutrophils in COPD (P < 0.05). SAA predominately promoted expression of the T(H)17 polarizing cytokine IL-6, which was opposed by 15-epi-lipoxin A(4), a counter-regulatory mediator, and ALX/FPR2 ligand. SAA-induced inflammation was markedly reduced by a neutralizing antibody to IL-17A in vivo. Cellular sources of IL-17A induced by SAA include CD4(+) T cells, gamma delta T cells, and an Epcam(+)CD45(-) population enriched for epithelial cells. SAA promotes expression of IL-17A in gamma delta T cells and this innate cell proportionally expressed higher levels of IL-17A transcript than CD4(+) T cells or epithelial cells.Conclusions: The SAA-IL-17A axis represents an important innate defense network that may underlie persistent neutrophilic airway inflammation in COPD and modulating the ALX/FPR2 receptor represents a novel approach to targeting aberrant IL-17A-mediated lung immunity.