Immunity：发现凋亡细胞吞噬和免疫耐受新机制
http://www.bio360.net/attachments/2016/03/145791806819729111c4b3207e.jpg近日，第三军医大学科研团队历时４年，在世界上首次发现促红细胞生成素能让吞噬细胞“胃口大开”，从而“吃”掉凋亡细胞，这将为治疗红斑狼疮等免疫性疾病提供新的途径。
此项研究成果已形成论文《巨噬细胞促红细胞生成素信号通路促进凋亡细胞吞噬清除及免疫耐受》，日前发表于国际著名期刊《免疫》。
据了解，人体内每天都会有大量细胞凋亡，这些细胞在生物学上被称为凋亡细胞。如果不及时清除凋亡细胞，它们就会释放出有害物质，刺激炎症细胞，从而引起炎症反应。幸运的是，人体内的吞噬细胞会“吃”掉这些凋亡细胞，起到抑制炎症的作用。
“吞噬细胞能否及时有效吃掉凋亡细胞，与系统性红斑狼疮、类风湿性关节炎等免疫性疾病，动脉粥样硬化等非消退性炎症相关疾病，均密切相关。”科研团队负责人张志仁教授介绍，因此，凋亡细胞吞噬清除机制是国际上重点关注的研究领域之一。
大量研究发现，凋亡细胞会释放一种名为“ｆｉｎｄｍｅ”（找到我）的信号分子，相当于食物的香味，来吸引吞噬细胞吃掉它。但这种分子是否能同时增加吞噬细胞对凋亡细胞的胃口，却无从得知。
２０１２年起，张志仁及其团队开始着手研究，在进行大量体外细胞实验和小鼠体内实验后发现，凋亡细胞分泌“ｆｉｎｄｍｅ”分子中的一个“成员”Ｓ１Ｐ分子，可诱导巨噬细胞产生促红细胞生成素及其受体。“巨噬细胞是吞噬细胞的一种，占吞噬细胞的多数。”张志仁解释，促红细胞生成素相当于是巨噬细胞胃口大门的“钥匙”，受体则是大门上的“锁”，用“钥匙”开了“锁”，巨噬细胞胃口增加了，就能“吃”掉更多凋亡细胞。在此基础上，研究人员进行了反复实验，他们敲除小鼠体内巨噬细胞上的促红细胞生成素受体，发现由于“锁”被敲掉，“钥匙”找不着“锁”，巨噬细胞没有了“胃口”，凋亡细胞增多，如此一来，小鼠会在无外因的条件下发生系统性红斑狼疮样病变，而促红细胞生成素治疗则可显著改善这一病变。
据介绍，该研究将为调控凋亡细胞吞噬清除提供新靶点，也为临床上多种与凋亡细胞吞噬清除障碍相关的慢性、难治性疾病的治疗提供新的途径。
来源：新华社
Erythropoeitin Signaling in Macrophages Promotes Dying Cell Clearance and Immune Tolerance
Bangwei Luo, Woting Gan, Zongwei Liu, Zigang Shen, Jinsong Wang, Rongchen Shi, Yuqi Liu, Yu Liu, Man Jiang, Zhiren Zhangcorrespondenceemail, Yuzhang Wu
Highlights
•Dying cell-released S1P activates macrophage EPO signaling in vitro and in vivo
•Macrophage EPO signaling is central for the immunosilent disposal of dying cells
•EPO enhances dying cell clearance through upregulating PPARγ in macrophages
•Macrophage-specific Epor−/− mice develope age-dependent lupus-like symptoms
Summary
The failure of apoptotic cell clearance is linked to autoimmune diseases, nonresolving inflammation, and developmental abnormalities; however, pathways that regulate phagocytes for efficient apoptotic cell clearance remain poorly known. Apoptotic cells release find-me signals to recruit phagocytes to initiate their clearance. Here we found that find-me signal sphingosine 1-phosphate (S1P) activated macrophage erythropoietin (EPO) signaling promoted apoptotic cell clearance and immune tolerance. Dying cell-released S1P activated macrophage EPO signaling. Erythropoietin receptor (EPOR)-deficient macrophages exhibited impaired apoptotic cell phagocytosis. EPO enhanced apoptotic cell clearance through peroxisome proliferator activated receptor-γ (PPARγ). Moreover, macrophage-specific Epor−/− mice developed lupus-like symptoms, and interference in EPO signaling ameliorated the disease progression in lupus-like mice. Thus, we have identified a pathway that regulates macrophages to clear dying cells, uncovered the priming function of find-me signal S1P, and found a role of the erythropoiesis regulator EPO in apoptotic cell disposal, with implications for harnessing dying cell clearance.
http://www.cell.com/immunity/fulltext/S1074-7613(16)00003-0
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