Combinatorial pattern recognition receptor signaling alters the balance of life and death in macrophages
Combinatorial pattern recognition receptor signaling alters the balance of life and death in macrophages
复制标题
DOI：
10.1073/pnas.0609671104
复制
发表时间：
2006-12-26
影响因子：
11.1
通讯作者：
Tabas, Ira
中科院分区：
文献类型：
--
作者：
Seimon, Tracie A.;Obstfeld, Amrom;Tabas, Ira
巨噬细胞模式识别受体（PRRs）在先天免疫中起关键作用，但在某些病理条件下，它们也可能参与疾病过程。我们最近发现，参与A型清道夫受体（SRA），PRR，触发JNK依赖性细胞凋亡的内质网（ER）应激的巨噬细胞。在晚期动脉粥样硬化病变中，在巨噬细胞中观察到SRA、活化的JNK和ER应激，并且晚期动脉粥样硬化中的巨噬细胞死亡导致斑块坏死。在此，我们发现SRA配体通过与另一种PRR，Toll样受体4（TLR 4）合作，将TLR 4信号从促存活重定向到促凋亡，从而触发ER应激巨噬细胞的凋亡。常见的SRA配体激活TLR 4信号传导并参与SRA。TLR 4效应导致TLR 4的促凋亡MyD 88-JNK分支的活化，而SRA效应使TLR 4的促存活IRF-3-IFN-β分支沉默。LPS诱导的TLR 4活化的正常细胞存活效应通过IFN-β的免疫中和转化为细胞凋亡反应，并且SRA配体的细胞凋亡效应通过与IFNI-P重建转化为细胞存活反应。因此，两种不同PRR之间的组合信号传导导致功能性结果-巨噬细胞凋亡，其不与单独的PRR一起发生。PRR诱导的巨噬细胞死亡可能在晚期动脉粥样硬化和其他先天免疫相关过程中发挥重要作用，其中巨噬细胞存活和死亡之间的平衡至关重要。
Macrophage pattern recognition receptors (PRRs) play key roles in innate immunity, but they also may contribute to disease processes under certain pathological conditions. We recently showed that engagement of the type A scavenger receptor (SRA), a PRR, triggers JNK-dependent apoptosis in endoplasmic reticullum (ER)-stressed macrophages. In advanced atherosclerotic lesions, the SRA, activated JNK, and ER stress are observed in macrophages, and macrophage death in advanced atheromata leads to plaque necrosis. Herein, we show that SRA ligands trigger apoptosis in ER-stressed macrophages by cooperating with another PRR, Toll-like receptor 4 (TLR4), to redirect TLR4 signaling from prosurvival to proapoptotic. Common SRA ligands activate both TLR4 signaling and engage the SRA. The TLR4 effect results in activation of the proapoptotic MyD88-JNK branch of TLR4, whereas the SRA effect silences the prosurvival IRF-3-IFN-beta branch of TLR4. The normal cell-survival effect of LPS-induced TLR4 activation is converted into an apoptosis response by immunoneutralization of IFN-beta, and the apoptosis effect of SRA ligands is converted into a cell-survival response by reconstitution with IFNI-P. Thus, combinatorial signaling between two distinct PRRs results in a functional outcome-macrophage apoptosis that does not occur with either PRR alone. PRR-induced macrophage death may play important roles in advanced atherosclerosis and in other innate immunity-related processes in which the balance between macrophage survival and death is critical.