Extracellular ATP-stimulated macrophages produce macrophage inflammatory protein-2 which is important for neutrophil migration
Extracellular ATP-stimulated macrophages produce macrophage inflammatory protein-2 which is important for neutrophil migration
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DOI：
10.1111/j.1365-2567.2012.03601.x
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发表时间：
2012-08-01
期刊：
影响因子：
6.4
通讯作者：
Abo, Toru
中科院分区：
文献类型：
--
作者：
Kawamura, Hiroki;Kawamura, Toshihiko;Abo, Toru
巨噬细胞是趋化因子巨噬细胞炎性蛋白-2(MIP-2)和角质形成细胞源性趋化因子(KC)的主要来源，它们在中性粒细胞向炎症部位的迁移中发挥重要作用。虽然炎症组织细胞外的ATP在巨噬细胞中诱导了多种免疫反应，但目前尚不清楚ATP刺激的巨噬细胞是否会影响中性粒细胞的迁移。因此，本研究的目的是探讨三磷酸腺苷诱导巨噬细胞产生MIP-2的作用。小鼠腹腔注射三磷酸腺苷后，腹腔内中性粒细胞数量明显增加，灌洗液中MIP-2和KC水平明显升高。与此一致的是，在体外，ATP诱导腹膜渗出液巨噬细胞(PEM)产生MIP-2，但不诱导KC的产生。这是通过与P2X7受体和P2Y2受体相互作用而发生的。此外，用三磷酸腺苷处理质子交换膜会产生活性氧物种。抗氧化剂N-乙酰-L-半胱氨酸可抑制三磷酸腺苷诱导的巨噬细胞炎性蛋白-2的产生。此外，用细胞外信号调节蛋白1/2或p38丝裂原活化蛋白激酶的抑制剂预先孵育PEM，可抑制MIP-2的产生。MIP-2的中和减少了在ATP处理的小鼠中观察到的中性粒细胞数量的增加。综上所述，这些结果表明，ATP刺激的巨噬细胞产生的活性氧增加，激活了促进MIP-2产生的信号通路，进而诱导中性粒细胞迁移。
Macrophages are the major source of the chemokines macrophage inflammatory protein-2 (MIP-2) and keratinocyte-derived chemokine (KC), which play a major role in neutrophil migration to sites of inflammation. Although extracellular ATP from inflammatory tissues induces several immune responses in macrophages, it is unclear whether ATP-stimulated macrophages affect neutrophil migration. Therefore, the aim of the present study was to investigate the role of ATP-induced MIP-2 production by macrophages. When ATP was injected intraperitoneally into mice, the number of neutrophils within the peritoneal cavity markedly increased, along with the levels of MIP-2 and KC in the peritoneal lavage fluid. Consistent with this, ATP induced MIP-2 production, but not that of KC, by peritoneal exudate macrophages (PEMs) in vitro. This occurred via interactions with the P2X7 receptor and P2Y2 receptor. Furthermore, treatment of PEMs with ATP led to the production of reactive oxygen species. The ATP-induced MIP-2 production was inhibited by treatment with the antioxidant N-acetyl-l-cysteine. Also, MIP-2 production was inhibited by pre-incubating PEMs with inhibitors of extracellular signal-regulated kinase 1/2 or p38 mitogen-activated protein kinase. The MIP-2 neutralization reduced the increase in neutrophil numbers observed in ATP-treated mice. Taken together, these results suggest that increased production of reactive oxygen species by ATP-stimulated macrophages activates the signalling pathways that promote MIP-2 production which, in turn, induces neutrophil migration.