Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Int Immunol. 2013 Nov;25(11):643-50. doi: 10.1093/intimm/dxt033. Epub 2013 Aug 29.
Efferocytosis, which is the homeostatic phagocytosis of apoptotic cells, prevents the release of toxic intracellular contents and subsequent tissue damage. Impairment of efferocytosis was reported in alveolar macrophages (AMs) of patients with chronic obstructive pulmonary disease (COPD), a common disease caused by smoking. In COPD, histone deacetylase (HDAC) activity is reduced in AMs. We investigated whether the reduction of HDAC activity is associated with the impairment of efferocytosis. Murine AMs were collected by bronchoalveolar lavage and their ability to efferocytose apoptotic human polymorphonuclear leukocytes was assessed. Pre-treatment of AMs with cigarette smoke extract (CSE) or trichostatin A (TSA), an HDAC inhibitor, suppressed efferocytosis and CSE reduced HDAC activity. TSA inhibited the activity of Rac, a key mediator of efferocytosis. These TSA-induced impairments were restored by treatment of AMs with aminophylline, a potent activator of HDAC. To further elucidate the underlying mechanism, we explored a role of CD9 in TSA-induced impairment of efferocytosis. CD9 is a transmembrane protein of the tetraspanin family that facilitates the uptake of several pathogens and other material. TSA profoundly down-regulated the expression of CD9 on AMs. The expression of CD9 was partly down-regulated by the Rac inhibitor. Pretreatment with an anti-CD9 mAb or CD9 small interfering RNA inhibited efferocytosis, which was attributable to the reduced binding of AMs to apoptotic cells. These results suggest that smoking impairs efferocytosis via inhibition of HDAC/Rac/CD9 pathways. Aminophylline/theophylline is effective in restoring the impairment of efferocytosis and might have benefit for the treatment of patients with COPD.
吞噬作用，即对凋亡细胞的稳态吞噬作用，可防止有毒细胞内容物的释放和随后的组织损伤。据报道，在慢性阻塞性肺疾病（COPD）患者的肺泡巨噬细胞（AMs）中，吞噬作用受损，COPD 是一种由吸烟引起的常见疾病。在 COPD 中，AMs 中的组蛋白去乙酰化酶（HDAC）活性降低。我们研究了 HDAC 活性的降低是否与吞噬作用受损有关。通过支气管肺泡灌洗收集小鼠 AMs，并评估其吞噬凋亡人多形核白细胞的能力。用香烟烟雾提取物（CSE）或组蛋白去乙酰化酶抑制剂（TSA）预处理 AMs，抑制吞噬作用，CSE 降低 HDAC 活性。TSA 抑制吞噬作用的关键介质 Rac 的活性。用氨茶碱（一种有效的 HDAC 激活剂）处理 AMs 可恢复 TSA 引起的这些损伤。为了进一步阐明潜在的机制，我们研究了 CD9 在 TSA 诱导的吞噬作用受损中的作用。CD9 是四跨膜蛋白家族的跨膜蛋白，可促进几种病原体和其他物质的摄取。TSA 可显著下调 AMs 上 CD9 的表达。Rac 抑制剂部分下调 CD9 的表达。用抗 CD9 mAb 或 CD9 siRNA 预处理可抑制吞噬作用，这归因于 AMs 与凋亡细胞的结合减少。这些结果表明，吸烟通过抑制 HDAC/Rac/CD9 途径损害吞噬作用。氨茶碱/茶碱可有效恢复吞噬作用受损，并可能有益于 COPD 患者的治疗。
