Unique expression of suppressor of cytokine signaling 3 is essential for classical macrophage activation in rodents in vitro and in vivo
Unique expression of suppressor of cytokine signaling 3 is essential for classical macrophage activation in rodents in vitro and in vivo
复制标题
细胞因子信号传导抑制剂 3 的独特表达对于啮齿动物体外和体内经典巨噬细胞激活至关重要
DOI：
10.4049/jimmunol.180.9.6270
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发表时间：
2008-05-01
影响因子：
4.4
通讯作者：
Wilson, Heather M.
中科院分区：
文献类型：
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作者：
Liu, Yu;Stewart, Keith N.;Wilson, Heather M.
在浸润性炎症组织上，巨噬细胞对局部微环境做出反应，并发展两种广泛的表型之一：引起组织损伤的经典激活(M1)巨噬细胞和促进修复的激活巨噬细胞。对这种极化在体内如何发生的了解还远未完全，在这项研究中，使用Th1介导的巨噬细胞依赖的急性肾小球肾炎、肾毒性肾炎模型，我们研究了细胞因子信号转导抑制因子(SOCS)1和SOCS3的作用。正常肾脏的巨噬细胞不表达可检测到的SOCS蛋白，但那些浸润性炎症肾小球的巨噬细胞迅速极化为表达SOCS1(27+/-6%)或SOCS3(54+/-12%)，但很少同时表达两者(10+/-3%)。大鼠骨髓来源的巨噬细胞与干扰素-γ或脂多糖共同孵育后表达SOCS1和SOCS3，而IL-4刺激的巨噬细胞仅表达SOCS1。相比之下，与干扰素-伽马和脂多糖共同孵育时，抑制SOCS1，同时将巨噬细胞独特地极化为表达SOCS3的细胞。被短干扰RNA敲除SOCS3的巨噬细胞对干扰素-γ和内毒素的反应非常不同：它们增强了STAT3的活性；诱导了巨噬细胞甘露糖受体、精氨酸酶和SOCS1；恢复了M1巨噬细胞抑制的IL-4反应；减少了炎症介质(NO和IL-6)和共刺激分子CD86的合成，表明SOCS3是M1激活所必需的。如果没有它，巨噬细胞在暴露于经典的激活刺激时会产生特征的交替激活的标志物。最后，肾毒性肾炎时肾小球IL-4的升高抑制了浸润性巨噬细胞SOCS3的表达，并与肾小球损伤程度减轻有关。因此，我们认为SOCS3在体外和体内对M1巨噬细胞的发育是必不可少的。
On infiltrating inflamed tissue, macrophages respond to the local microenvironment and develop one of two broad phenotypes: classically activated (M1) macrophages that cause tissue injury and alternatively activated macrophages that promote repair. Understanding how this polarization occurs in vivo is far from complete, and in this study, using a Th1-mediated macrophage-dependent model of acute glomerulonephritis, nephrotoxic nephritis, we examine the role of suppressor of cytokine signaling (SOCS)1 and SOCS3. Macrophages in normal kidneys did not express detectable SOCS proteins but those infiltrating inflamed glomeruli were rapidly polarized to express either SOCS1 (27 +/- 6%) or SOCS3 (54 +/- 12%) but rarely both (10 +/- 3%). Rat bone marrow-derived macrophages incubated with IFN-gamma or LPS expressed SOCS1 and SOCS3, whereas IL-4 stimulated macrophages expressed SOCS1 exclusively. By contrast, incubation with IFN-gamma and LPS together suppressed SOCS1 while uniquely polarizing macrophages to SOCS3 expressing cells. Macrophages in which SOCS3 was knocked down by short interfering RNA responded to IFN-gamma and LPS very differently: they had enhanced STAT3 activity; induction of macrophage mannose receptor, arginase and SOCS1; restoration of IL-4 responsiveness that is inhibited in M1 macrophages; and decreased synthesis of inflammatory mediators (NO and IL-6) and costimulatory molecule CD86, demonstrating that SOCS3 is essential for M1 activation. Without it, macrophages develop characteristic alternatively activated markers when exposed to classical activating stimuli. Lastly, increased glomerular IL-4 in nephrotoxic nephritis inhibits infiltrating macrophages from expressing SOCS3 and was associated with attenuated glomerular injury. Consequently, we propose that SOCS3 is essential for development of M1 macrophages in vitro and in vivo.