Free radical-producing myeloid-derived regulatory cells: potent activators and suppressors of lung inflammation and airway hyperresponsiveness
Free radical-producing myeloid-derived regulatory cells: potent activators and suppressors of lung inflammation and airway hyperresponsiveness
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DOI：
10.1038/mi.2011.16
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发表时间：
2011-09-01
影响因子：
8
通讯作者：
Chaplin, D. D.
中科院分区：
文献类型：
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作者：
Deshane, J.;Zmijewski, J. W.;Chaplin, D. D.
哮喘发作时气道中活性自由基水平升高，但其在哮喘病理生理中的作用尚不清楚。我们已经鉴定出骨髓源性抑制样细胞亚群是实验性变应性气道炎症小鼠肺部一氧化氮和超氧化物的关键来源，并确定这些细胞是气道炎症反应的主要调节因子。它们产生的自由基谱依赖于诱导型一氧化氮合酶（iNOS）、精氨酸酶和烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶的表达。这些自由基控制了这些细胞的促炎和抗炎潜能，并调节了它们浸润到肺部的互惠模式。产生一氧化氮的细胞是Ly-6C（+）和Ly-6G(-)，它们下调t细胞激活，募集T-reg细胞，并显著下调抗原诱导的气道高反应性。产生超氧化物的细胞是Ly-6C（-）和Ly-6G(+)，它们表达促炎活性，以超氧化物依赖的方式加剧气道的高反应性。较小数量的Ly-6C（+）和Ly-6G（+）细胞也抑制t细胞反应，但以不依赖于iNOS和精氨酸酶的方式。这些调节性骨髓细胞是哮喘治疗的重要靶点。
Levels of reactive free radicals are elevated in the airway during asthmatic exacerbations, but their roles in the pathophysiology of asthma remain unclear. We have identified subsets of myeloid-derived suppressor-like cells as key sources of nitric oxide and superoxide in the lungs of mice with evolving experimental allergic airway inflammation and established these cells as master regulators of the airway inflammatory response. The profiles of free radicals they produced depended on expression of inducible nitric oxide synthase (iNOS), arginase, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. These radicals controlled the pro-and anti-inflammatory potential of these cells, and also regulated the reciprocal pattern of their infiltration into the lung. The nitric oxide-producing cells were Ly-6C(+)Ly-6G(-) and they downmodulated T-cell activation, recruited T-reg cells, and dramatically downregulated antigen-induced airway hyperresponsiveness. The superoxide-producing cells were Ly-6C(-)Ly-6G(+) and they expressed proinflammatory activities, exacerbating airway hyperresponsiveness in a superoxide-dependent fashion. A smaller population of Ly-6C(+)Ly-6G(+) cells also suppressed T-cell responses, but in an iNOS- and arginase-independent fashion. These regulatory myeloid cells represent important targets for asthma therapy.