IFNγ is a Key Link between Obesity and Th1-Mediated AutoImmune Diseases.
IFNγ is a Key Link between Obesity and Th1-Mediated AutoImmune Diseases.
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DOI：
10.3390/ijms22010208
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发表时间：
2020-12-28
影响因子：
5.6
通讯作者：
Kwon EY
中科院分区：
文献类型：
--
作者：
Bae HR;Choi MS;Kim S;Young HA;Gershwin ME;Jeon SM;Kwon EY
肥胖是代谢综合征的一个特征，也与慢性炎症和自身免疫性疾病的发展有关。然而，肥胖与自身免疫性疾病之间的关系仍有待深入研究。在这里，我们使用基于干扰素γ (IFNγ)慢性表达的原发性胆管炎（PBC）小鼠模型（ARE-Del-/-小鼠）比较了高脂肪饮食（HFD）小鼠的肝脏基因表达谱。受上游转录调节因子IFNγ、LPS和TNFα影响的最高差异表达基因在HFD和re - del -/-小鼠中显示重叠，表明肥胖诱导的肝脏炎症可能依赖于ifn - γ的信号传导。HFD小鼠改变的顶端通路主要参与先天免疫应答，与ARE-Del-/-小鼠重叠。相反，T细胞介导的信号通路在ARE-Del-/-小鼠中完全改变。我们进一步评估了木犀草素（被称为抗炎类黄酮）在HFD和ARE-Del-/-小鼠中的治疗效果。木犀草素强烈抑制MHC I和II抗原呈递途径，这些途径在HFD和ARE-Del-/-小鼠中高度激活。相反，木犀草素增加了肝脏中脂肪酸氧化和氧化磷酸化的代谢过程，而这些过程在ARE-Del-/-小鼠中被抑制。木犀草素还能强烈诱导PPAR信号通路，在HFD和ARE-Del-/-小鼠中，PPAR信号通路下调。利用人类GWAS数据，我们表征了重要的肥胖相关基因与IFNγ信号传导之间的遗传相互作用，并证明IFNγ对肥胖介导的炎症反应至关重要。总的来说，这项研究提高了我们对肥胖和自身免疫性疾病之间关系的机制理解。此外，它为基于免疫网络的分析如何有效地整合RNA-seq和微阵列数据提供了新的方法见解。
Obesity, a characteristic of metabolic syndrome, is also associated with chronic inflammation and the development of autoimmune diseases. However, the relationship between obesity and autoimmune diseases remains to be investigated in depth. Here, we compared hepatic gene expression profiles among high-fat diet (HFD) mice using the primary biliary cholangitis (PBC) mouse model based on the chronic expression of interferon gamma (IFNγ) (ARE-Del-/- mice). The top differentially expressed genes affected by upstream transcriptional regulators IFNγ, LPS, and TNFα displayed an overlap in HFD and ARE-Del-/- mice, indicating that obesity-induced liver inflammation may be dependent on signaling via IFNγ. The top pathways altered in HFD mice were mostly involved in the innate immune responses, which overlapped with ARE-Del-/- mice. In contrast, T cell-mediated signaling pathways were exclusively altered in ARE-Del-/- mice. We further evaluated the therapeutic effect of luteolin, known as anti-inflammatory flavonoid, in HFD and ARE-Del-/- mice. Luteolin strongly suppressed the MHC I and II antigen presentation pathways, which were highly activated in both HFD and ARE-Del-/- mice. Conversely, luteolin increased metabolic processes of fatty acid oxidation and oxidative phosphorylation in the liver, which were suppressed in ARE-Del-/- mice. Luteolin also strongly induced PPAR signaling, which was downregulated in HFD and ARE-Del-/- mice. Using human GWAS data, we characterized the genetic interaction between significant obesity-related genes and IFNγ signaling and demonstrated that IFNγ is crucial for obesity-mediated inflammatory responses. Collectively, this study improves our mechanistic understanding of the relationship between obesity and autoimmune diseases. Furthermore, it provides new methodological insights into how immune network-based analyses effectively integrate RNA-seq and microarray data.
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影响因子：
12.8
作者：
Hodge DL;Berthet C;Coppola V;Kastenmüller W;Buschman MD;Schaughency PM;Shirota H;Scarzello AJ;Subleski JJ;Anver MR;Ortaldo JR;Lin F;Reynolds DA;Sanford ME;Kaldis P;Tessarollo L;Klinman DM;Young HA
通讯作者：
Young HA
影响因子：
13.5
作者：
Bae, Heekyong R.;Leung, Patrick S. C.;Tsuneyama, Koichi;Valencia, Julio C.;Hodge, Deborah L.;Kim, Seohyun;Back, Tim;Karwan, Megan;Merchant, Anand S.;Baba, Nobuyuki;Feng, Dechun;Park, Ogyi;Gao, Bin;Yang, Guo-Xiang;Gershwin, M. Eric;Young, Howard A.
通讯作者：
Young, Howard A.
影响因子：
7.3
作者：
Diskin C;Pålsson-McDermott EM
通讯作者：
Pålsson-McDermott EM
影响因子：
44.1
作者：
通讯作者：
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影响因子：
12.8
作者：
Bae, Heekyong R.;Leung, Patrick S. C.;Young, Howard A.
通讯作者：
Young, Howard A.