IFN Regulatory Factor 2 Inhibits Expression of Glycolytic Genes and Lipopolysaccharide-Induced Proinflammatory Responses in Macrophages.
IFN Regulatory Factor 2 Inhibits Expression of Glycolytic Genes and Lipopolysaccharide-Induced Proinflammatory Responses in Macrophages.
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DOI：
10.4049/jimmunol.1701571
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发表时间：
2018-05-01
期刊：
影响因子：
--
通讯作者：
Liu G
中科院分区：
文献类型：
--
作者：
Cui H;Banerjee S;Guo S;Xie N;Liu G
巨噬细胞中炎症反应的快速启动和及时消退是协同事件，已知其对于针对病原体感染的最佳宿主防御同样至关重要。然而，这些过程的调节，特别是通过特定的细胞代谢程序，还没有得到很好的理解。在这项研究中，我们发现，干扰素调节因子2（IRF 2）在LPS处理的小鼠巨噬细胞蛋白酶体介导的途径经历了早期降解，随后通过反式激活的表达恢复。我们发现IRF 2是抗炎的，因为该蛋白的敲低促进LPS诱导的促炎介质。从机制上讲，虽然IRF 2显然不靶向LPS接合后的近端细胞质信号传导事件，但它抑制了糖酵解基因的HIF-1α依赖性表达，从而抑制了细胞糖酵解，这是IRF 2抗炎活性所必需的连续事件。我们发现内毒素耐受状态的巨噬细胞表现出LPS增强糖酵解的缺陷，这可能是由于IRF 2下调失败以及这些细胞中糖酵解基因随后上调所致。与LPS的观察相反，IRF 2的敲低降低了IL-4诱导的巨噬细胞交替激活。IRF 2的pro-IL-4活性依赖于KLF 4，KLF 4是IRF 2转录诱导的交替激活的关键介质。总之，我们的数据表明，IRF 2是一个重要的调节因子，通过控制HIF-1α依赖的糖酵解基因的表达和糖酵解在巨噬细胞的促炎反应。该研究还表明IRF 2是治疗与巨噬细胞活化失调相关的炎症性疾病的新治疗靶点。
Rapid initiation and timely resolution of inflammatory response in macrophages are synergistic events that are known to be equally critical to optimal host defense against pathogen infections. However, the regulation of these processes, in particular by specific cellular metabolic program, has not been well understood. In this study, we found that interferon regulatory factor 2 (IRF2) underwent an early degradation in a proteasome-mediated pathway in LPS treated mouse macrophages, followed by a later recovery of the expression via transactivation. We showed that IRF2 was anti-inflammatory in that knockdown of this protein promoted LPS induced pro-inflammatory mediators. Mechanistically, while IRF2 apparently did not target the proximal cytoplasmic signaling events upon LPS engagements, it inhibited HIF-1α dependent expression of glycolytic genes and thereby cellular glycolysis, sequential events necessary for the IRF2 anti-inflammatory activity. We found that macrophages in endotoxin tolerant state demonstrated deficiency in LPS augmented glycolysis, which was likely caused by failed downregulation of IRF2 and the ensuing upregulation of the glycolytic genes in these cells. In contrast to observations with LPS, knockdown of IRF2 decreased IL-4 induced macrophage alternative activation. The pro-IL-4 activity of IRF2 was dependent on KLF4, a key mediator of the alternative activation, which was transcriptionally induced by IRF2. In conclusion, our data suggest that IRF2 is an important regulator of the pro-inflammatory response in macrophages by controlling HIF-1α dependent glycolytic gene expression and glycolysis. This study also indicates IRF2 as a novel therapeutic target to treat inflammatory disorders associated with dysregulations of macrophage activations.
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影响因子：
30.5
作者：
通讯作者：
--
DOI：
10.4049/jimmunol.1202496
发表时间：
2013-06-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Banerjee S;Xie N;Cui H;Tan Z;Yang S;Icyuz M;Abraham E;Liu G
通讯作者：
Liu G
影响因子：
64.5
作者：
Chang CH;Curtis JD;Maggi LB Jr;Faubert B;Villarino AV;O'Sullivan D;Huang SC;van der Windt GJ;Blagih J;Qiu J;Weber JD;Pearce EJ;Jones RG;Pearce EL
通讯作者：
Pearce EL
影响因子：
32.4
作者：
Hida, S;Ogasawara, K;Taniguchi, T
通讯作者：
Taniguchi, T
影响因子：
4.8
作者：
Liu, Gang;Park, Young-Jun;Abraham, Edward
通讯作者：
Abraham, Edward