Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294; and.
Department of Pulmonary, Allergy, and Critical Care Medicine, Second Affiliated Hospital, Tianjin University of Traditional Chinese Medicine, Tianjin 300150, China.
J Immunol. 2018 May 1;200(9):3218-3230. doi: 10.4049/jimmunol.1701571. Epub 2018 Mar 21.
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 a specific cellular metabolic program, has not been well understood. In this study, we found that IFN 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 the production of LPS-induced proinflammatory mediators. Mechanistically, although 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 proinflammatory 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.
在巨噬细胞中，炎症反应的快速启动和及时解决是协同事件，这对于宿主对抗病原体感染的最佳防御同样至关重要。然而，这些过程的调节，特别是通过特定的细胞代谢程序的调节，尚未得到很好的理解。在这项研究中，我们发现 IFN 调节因子 2（IRF2）在 LPS 处理的小鼠巨噬细胞中通过蛋白酶体介导的途径早期降解，随后通过反式激活恢复表达。我们表明，IRF2 具有抗炎作用，因为该蛋白的敲低促进了 LPS 诱导的促炎介质的产生。从机制上讲，尽管 IRF2 显然没有针对 LPS 结合后的细胞质信号事件的近端靶向，但它抑制了 HIF-1α 依赖性糖酵解基因的表达，从而抑制了细胞糖酵解，这是 IRF2 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 增强的糖酵解缺陷，这可能是由于 IRF2 下调失败和随后这些细胞中糖酵解基因的上调所致。与 LPS 的观察结果相反，IRF2 的敲低减少了 IL-4 诱导的巨噬细胞替代激活。IRF2 的促 IL-4 活性依赖于 KLF4，KLF4 是替代激活的关键介质，它被 IRF2 转录诱导。总之，我们的数据表明，IRF2 通过控制 HIF-1α 依赖性糖酵解基因表达和糖酵解，是巨噬细胞中促炎反应的重要调节因子。本研究还表明，IRF2 是一种治疗与巨噬细胞激活失调相关的炎症性疾病的新的治疗靶点。
