GAT107，一种新型 α7 烟碱乙酰胆碱受体激动剂正变构调节剂，可恢复高氧受损的巨噬细胞功能,Free Radical Biology and Medicine

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GAT107，一种新型 α7 烟碱乙酰胆碱受体激动剂正变构调节剂，可恢复高氧受损的巨噬细胞功能
Free Radical Biology and Medicine ( IF 7.1 ) Pub Date : 2016-11-01 , DOI: 10.1016/j.freeradbiomed.2016.10.143
Alex Gauthier

巨噬细胞是抵御入侵病原体的第一道防线。然而，长时间暴露于高氧环境会损害它们吞噬和杀死细菌的能力。长时间暴露于高氧 (≥95% O2) 会导致核 HMGB1 释放到细胞外环境中，其中 HMGB1 作为一种有效的促炎细胞因子并抑制巨噬细胞的功能 (2)。自主神经系统的迷走神经调节促炎细胞因子的分泌，因此可能调节 HMGB1 介导的损伤。激动剂与 α7nAchR 的正构位点结合，在高浓度下可能会导致脱敏，并会破坏受体的内源性张力。使用 α7nAchR 的 ago-PAM（正变构调节剂）可以协同和增强正构位点介导的信号传导，而不会破坏内源性信号传导。我们测试了 GAT107（一种新的 ago-PAM）是否可以（1）减少高氧诱导的巨噬细胞 HMGB1 释放和（2）改善高氧受损的巨噬细胞吞噬作用。RAW 264.7 细胞是一种巨噬细胞样细胞系，在暴露于 95% O2 之前，先暴露于不同浓度的 GAT107。结果表明，微量浓度（1.1 和 3.3μM）的 GAT107 提高了高氧损害巨噬细胞的吞噬能力。此外，在相同浓度下，它在对细胞无毒的浓度下有效抑制氧化应激诱导的核 HMGB1 释放到细胞外环境。这些数据表明，GAT107 可以通过抑制核 HMGB1 释放到细胞外环境中来改善高氧损害的吞噬作用。所以，

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GAT107, a Novel Agonistic Positive Allosteric Modulator of α7 Nicotinic Acetylcholine Receptor Restores Hyperoxia-Compromised Macrophage Function

Macrophages are the first line of defense against invading pathogens. However, exposure to prolonged hyperoxia compromises their ability to phagocytose and kill bacteria. Exposure to prolonged hyperoxia (≥95% O2) leads to the release of nuclear HMGB1 into the extracellular milieu, where HMGB1 acts as a potent proinflammatory cytokine and suppresses macrophage’s functions (2). The vagus nerve of the autonomous nervous system regulates the secretion of proinflammatory cytokines, thus may modulate HMGB1-mediated damage. Agonists bind to the orthosteric site of α7nAchR and at high concentrations may cause desensitization and can disrupt the endogeous tone of the receptor. Use of ago-PAM (positive allosteric modulator) of the α7nAchR can synergize and enhance orthosteric site mediated signaling without disrupting the endogenous signaling. We tested whether GAT107 (a novel ago-PAM) can (1) decrease hyperoxia-induced HMGB1 release from macrophages and (2) improve hyperoxia-compromised macrophage phagocytosis. RAW 264.7 cells, a macrophage like cell line, were exposed to different concentrations of GAT107 prior to exposure to 95% O2. The results show that GAT107 at trace concentrations (1.1 and 3.3μM) improved hyperoxia-compromised phagocytic ability of macrophages. In addition, at the same concentrations it effectively inhibits oxidative stress-induced release of nuclear HMGB1 to the extracellular milieu at concentrations that are non-toxic to the cells. These data indicate that GAT107 can improve hyperoxia-compromised phagocytosis via inhibiting nuclear HMGB1 release into the extracellular milieu. Therefore, targeting α7nAchR using GAT107 may be a possible novel pharmacological agent that can be used to mediate proinflammatory reflex in macrophages.

更新日期：2016-11-01

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