Local apoptosis mediates clearance of macrophages from resolving inflammation in mice
Local apoptosis mediates clearance of macrophages from resolving inflammation in mice
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DOI：
10.1182/blood-2013-01-478206
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发表时间：
2013-10-10
期刊：
影响因子：
20.3
通讯作者：
Randolph, Gwendalyn J.
中科院分区：
文献类型：
--
作者：
Gautier, Emmanuel L.;Ivanov, Stoyan;Randolph, Gwendalyn J.
慢性炎性疾病如动脉粥样硬化的特征在于巨噬细胞的积聚。为了设计在疾病期间减少巨噬细胞负担的疗法，理解调节巨噬细胞从炎症消退部位去除的细胞和分子机制至关重要。尽管过去的研究已经考虑了巨噬细胞的局部死亡或它们从炎症灶中迁移的可能性，但从未采用量化死亡或迁移的方法。在这里，我们应用定量竞争的方法和其他方法来研究巯基乙酸盐诱导的腹膜炎，模型中，早期的工作表明，迁移到淋巴结的巨噬细胞清除。我们发现，转移到淋巴结发生在CC趋化因子受体7独立的方式，但总体而言，有一个定量的微小作用，在清除巨噬细胞。阻止迁移不会显著延迟消退。然而，当抵抗死亡的巨噬细胞与对照巨噬细胞竞争时，巨噬细胞池的收缩在抗凋亡细胞中延迟。这些数据反驳了巨噬细胞主要通过迁移清除的观点，并表明局部死亡控制着巨噬细胞的清除。这一发现改变了对与巨噬细胞积累相关的慢性疾病中哪些细胞过程值得靶向的强调。
Chronic inflammatory diseases such as atherosclerosis are characterized by an accumulation of macrophages. To design therapies that would reduce macrophage burden during disease, understanding the cellular and molecular mechanisms that regulate macrophage removal from sites of resolving inflammation is critical. Although past studies have considered the local death of macrophages or the possibility that they emigrate out of inflammatory foci, methods to quantify death or emigration have never been employed. Here, we applied quantitative competition approaches and other methods to study resolution of thioglycollate-induced peritonitis, the model in which earlier work indicated that emigration to lymph nodes accounted for macrophage removal. We show that migration to lymph nodes occurred in a CC chemokine receptor 7-independent manner but, overall, had a quantitativelyminor role in the removal of macrophages. Blocking migration did not significantly delay resolution. However, when macrophages resistant to death were competed against control macrophages, contraction of the macrophage pool was delayed in the apoptosis-resistant cells. Thesedata refute the concept thatmacrophages are dominantly cleared through emigration and indicate that local death controls macrophage removal. This finding alters the emphasis on which cellular processes merit targeting in chronic diseases associated with accumulation of macrophages.