Complement Protein C1q and Adiponectin Stimulate Mer Tyrosine Kinase-Dependent Engulfment of Apoptotic Cells through a Shared Pathway
Complement Protein C1q and Adiponectin Stimulate Mer Tyrosine Kinase-Dependent Engulfment of Apoptotic Cells through a Shared Pathway
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DOI：
10.1159/000363295
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发表时间：
2014-01-01
影响因子：
5.3
通讯作者：
Bohlson, Suzanne S.
中科院分区：
文献类型：
--
作者：
Galvan, Manuel D.;Hulsebus, Holly;Bohlson, Suzanne S.
未能清除凋亡细胞与发育和自身免疫缺陷有关。补体成分 C1q 是有效吞噬凋亡细胞（胞吞作用）所必需的，C1q 缺乏会导致狼疮的发生。我们最近发现了小鼠巨噬细胞中 C1q 依赖性胞吞作用的新分子机制。 C1q 引发 Mer 酪氨酸激酶 (Mer) 的表达，Mer 是一种调节有效胞吞作用和预防自身免疫的受体。为了表征 C1q 依赖性信号转导机制，对 C1q 激活巨噬细胞的转录组进行了通路分析，结果发现脂联素信号通路随 C1q 显着上调。脂联素在结构上与 C1q 同源，通过下游 5' 腺苷单磷酸激活蛋白激酶 (AMPK) 的激活来调节细胞代谢。 C1q 刺激巨噬细胞导致 AMPK 激活，并通过 siRNA 抑制 C1q 依赖性胞吞作用沉默 AMPK 表达。脂联素信号传导还会刺激核受体的激活，而核受体视黄醇 X 受体的抑制会消除 C1q 依赖性 Mer 表达和胞吞作用。此外，脂联素在巨噬细胞中引发 Mer 表达和 Mer 依赖性胞吞作用，与 C1q 刺激的细胞类似。总的来说，我们的结果表明，C1q 和脂联素共享一个共同的信号转导级联，以促进凋亡细胞的清除，并确定有效胞吞作用所需的新分子途径。 (C) 2014 S. Karger AG，巴塞尔
The failure to clear apoptotic cells is linked to defects in development and autoimmunity. Complement component C1q is required for efficient engulfment of apoptotic cells (efferocytosis), and C1q deficiency leads to the development of lupus. We recently identified a novel molecular mechanism for C1q-dependent efferocytosis in murine macrophages. C1q elicited the expression of Mer tyrosine kinase (Mer), a receptor that regulates efficient efferocytosis and prevention of autoimmunity. To characterize the C1q-dependent signal transduction mechanism, pathway analysis of the transcriptome from C1q-activated macrophages was performed, and it identified the adiponectin signaling pathway as significantly upregulated with C1q. Adiponectin is structurally homologous to C1q and regulates cellular metabolism via downstream activation of 5'adenosine monophosphate-activated protein kinase (AMPK). Macrophage stimulation with C1q resulted in the activation of AMPK, and silencing of AMPK expression using siRNA-inhibited C1q-de-pendent efferocytosis. Adiponectin signaling also stimulates activation of nuclear receptors, and inhibition of the nuclear receptor retinoid X receptor abrogated C1q-dependent Mer expression and efferocytosis. Furthermore, adiponectin elicited Mer expression and Mer-dependent efferocytosis in macrophages similar to cells stimulated with C1q. Collectively, our results suggest that C1q and adiponectin share a common signal transduction cascade to promote clearance of apoptotic cells, and identify a novel molecular pathway required for efficient efferocytosis. (C) 2014 S. Karger AG, Basel