Molecular Mechanism for Adiponectin-dependent M2 Macrophage Polarization LINK BETWEEN THE METABOLIC AND INNATE IMMUNE ACTIVITY OF FULL-LENGTH ADIPONECTIN
Molecular Mechanism for Adiponectin-dependent M2 Macrophage Polarization LINK BETWEEN THE METABOLIC AND INNATE IMMUNE ACTIVITY OF FULL-LENGTH ADIPONECTIN
复制标题
DOI：
10.1074/jbc.m110.204644
复制
发表时间：
2011-04-15
影响因子：
4.8
通讯作者：
Nagy, Laura E.
中科院分区：
文献类型：
--
作者：
Mandal, Palash;Pratt, Brian T.;Nagy, Laura E.
球状脂联素（gAcrp）的抗炎作用是通过IL-10/血红素加氧酶1（HO-1）依赖性途径介导的。虽然全长脂联素（flAcrp）也抑制LPS诱导的促炎信号，其信号转导机制尚未了解。本研究的目的是检查gAcrp和flAcrp抑制巨噬细胞中促炎信号传导的差异机制。慢性乙醇喂养增加LPS刺激的库普弗细胞TNF-α表达，与M1巨噬细胞极化的转变有关。gAcrp和flAcrp均抑制库普弗细胞中TNF-α的表达;然而，只有gAcrp的作用依赖于IL-10。类似地，在RAW 264.7巨噬细胞中抑制HO-1活性或siRNA敲低HO-1仅部分减弱flAcrp对MyD 88依赖性和非依赖性细胞因子特征的抑制作用。相反，flAcrp通过脂联素R2受体起作用，有效地将枯否细胞和RAW 264.7巨噬细胞的极化转变为M2表型。通过脂联素R1受体起作用的gAcrp在引起M2型基因表达方面的效果要差得多。M2极化也部分依赖于AMP激活的激酶。flAcrp在IL-4/STAT 6依赖性机制中将RAW 264.7巨噬细胞极化为M2表型。flAcrp还增加RAW 264.7巨噬细胞中参与氧化磷酸化的基因的表达，类似于flAcrp对肝细胞的作用。总之，这些数据表明，gAcrp和flAcrp利用差异信号传导策略来降低巨噬细胞对TLR 4配体激活的敏感性，其中flAcrp利用IL-4/STAT 6依赖性机制来将巨噬细胞极化转变为M2/抗炎表型。
The anti-inflammatory effects of globular adiponectin (gAcrp) are mediated by IL-10/heme oxygenase 1 (HO-1)-dependent pathways. Although full-length (flAcrp) adiponectin also suppresses LPS-induced pro-inflammatory signaling, its signaling mechanisms are not yet understood. The aim of this study was to examine the differential mechanisms by which gAcrp and flAcrp suppress pro-inflammatory signaling in macrophages. Chronic ethanol feeding increased LPS-stimulated TNF-alpha expression by Kupffer cells, associated with a shift to an M1 macrophage polarization. Both gAcrp and flAcrp suppressed TNF-alpha expression in Kupffer cells; however, only the effect of gAcrp was dependent on IL-10. Similarly, inhibition of HO-1 activity or siRNA knockdown of HO-1 in RAW264.7 macrophages only partially attenuated the suppressive effects of flAcrp on MyD88-dependent and -independent cytokine signatures. Instead, flAcrp, acting via the adiponectin R2 receptor, potently shifted the polarization of Kupffer cells and RAW264.7 macrophages to an M2 phenotype. gAcrp, acting via the adiponectin R1 receptor, was much less effective at eliciting an M2 pattern of gene expression. M2 polarization was also partially dependent on AMP-activated kinase. flAcrp polarized RAW264.7 macrophages to an M2 phenotype in an IL-4/STAT6-dependent mechanism. flAcrp also increased the expression of genes involved in oxidative phosphorylation in RAW264.7 macrophages, similar to the effect of flAcrp on hepatocytes. In summary, these data demonstrate that gAcrp and flAcrp utilize differential signaling strategies to decrease the sensitivity of macrophages to activation by TLR4 ligands, with flAcrp utilizing an IL-4/STAT6-dependent mechanism to shift macrophage polarization to the M2/anti-inflammatory phenotype.