Department of Biochemistry and Molecular Biology, Signaling and Apoptosis Research Group, Hungarian Academy of Sciences, Research Center of Molecular Medicine, University of Debrecen, Debrecen H-4012, Hungary.
J Immunol. 2011 Jun 15;186(12):7144-55. doi: 10.4049/jimmunol.1002284. Epub 2011 May 18.
Efficient execution of apoptotic cell death followed by efficient clearance mediated by professional macrophages is a key mechanism in maintaining tissue homeostasis. Removal of apoptotic cells usually involves three central elements: 1) attraction of phagocytes via soluble "find me" signals, 2) recognition and phagocytosis via cell surface-presenting "eat me" signals, and 3) suppression or initiation of inflammatory responses depending on additional innate immune stimuli. Suppression of inflammation involves both direct inhibition of proinflammatory cytokine production and release of anti-inflammatory factors, which all contribute to the resolution of inflammation. In the current study, using wild-type and adenosine A(2A) receptor (A2AR) null mice, we investigated whether A2ARs, known to mediate anti-inflammatory signals in macrophages, participate in the apoptotic cell-mediated immunosuppression. We found that macrophages engulfing apoptotic cells release adenosine in sufficient amount to trigger A2ARs, and simultaneously increase the expression of A2ARs, as a result of possible activation of liver X receptor and peroxisome proliferators activated receptor δ. In macrophages engulfing apoptotic cells, stimulation of A2ARs suppresses the NO-dependent formation of neutrophil migration factors, such as macrophage inflammatory protein-2, using the adenylate cyclase/protein kinase A pathway. As a result, loss of A2ARs results in elevated chemoattractant secretion. This was evident as pronounced neutrophil migration upon exposure of macrophages to apoptotic cells in an in vivo peritonitis model. Altogether, our data indicate that adenosine is one of the soluble mediators released by macrophages that mediate engulfment-dependent apoptotic cell suppression of inflammation.
凋亡细胞的有效执行，随后被专业的巨噬细胞介导的有效清除，是维持组织内稳态的关键机制。凋亡细胞的清除通常涉及三个核心要素：1）通过可溶性“寻我”信号吸引吞噬细胞，2）通过细胞表面呈现的“吃我”信号识别和吞噬，以及 3）根据额外的先天免疫刺激抑制或启动炎症反应。炎症的抑制既涉及对促炎细胞因子产生和释放的直接抑制，也涉及抗炎因子的释放，所有这些都有助于炎症的消退。在本研究中，我们使用野生型和腺苷 A(2A)受体（A2AR）缺失小鼠，研究了已知在巨噬细胞中介导抗炎信号的 A2AR 是否参与凋亡细胞介导的免疫抑制。我们发现，吞噬凋亡细胞的巨噬细胞释放出足够数量的腺苷来触发 A2AR，同时由于可能激活肝 X 受体和过氧化物酶体增殖物激活受体 δ，A2AR 的表达增加。在吞噬凋亡细胞的巨噬细胞中，A2AR 的刺激通过腺苷酸环化酶/蛋白激酶 A 途径抑制一氧化氮依赖性中性粒细胞迁移因子（如巨噬细胞炎症蛋白-2）的形成。因此，A2AR 的缺失导致趋化因子分泌增加。这在体内腹膜炎模型中巨噬细胞暴露于凋亡细胞时表现为明显的中性粒细胞迁移增加。总之，我们的数据表明，腺苷是巨噬细胞释放的可溶性介质之一，介导吞噬作用依赖性凋亡细胞抑制炎症。
