Macrophage Redox State in Sterilizing and Injurious Inflammation

本项目主要研究先天免疫极化的基本机制， 反应巨噬细胞是负责先天免疫极化的主要细胞类型 通过引发和传播炎症（M1表型）或解决炎症以促进 组织愈合（M2表型）。一个相对较新的观点是巨噬细胞极化的失调 随着M1超过M2表型的流行， 损伤在肺的情况下，急性肺损伤（ALI）可演变为急性呼吸窘迫综合征 急性呼吸窘迫综合征（ARDS），一种高度致命的呼吸衰竭形式。因此，了解 巨噬细胞分化成功能不同的表型可能会导致新的治疗策略， 预防或治疗ARDS。核因子κB（NFκB）是炎症反应的主要调节因子， 负责促进或解决炎症的基因表达。当p65/p50 NFκB构型促进炎症，p50/p50构型促进消退。我们 这是因为这些结构也调节巨噬细胞如何分化成不同的表型。在 关于这一点，我们最近发现，细胞因子信号转导抑制因子-1（SOCS 1）可能在 NFκB功能的转换，因为它靶向细胞核p65而不是p50降解，从而改变相对 核中这些组成亚基的丰度。SOCS 1敏感的发现 通过一氧化氮（NO）和可能其它活性物质的抑制也表明了新的分子 SOCS 1活性、NFκB功能、促炎和抗炎转录以及 因为巨噬细胞极化和炎症结果受到调节。这些机制是 我们的三个主要目标是：（1）确定SOCS 1促进NFκB的机制 从促炎转录复合物的功能转换为抗炎转录复合物的功能;（2） 确定巨噬细胞细胞内氧化还原状态的变化是否影响SOCS 1活性和NFκB 作为转录因子发挥作用;（3）确定SOCS 1在不同免疫细胞中的表达 在小鼠模型中， 细菌性肺炎

The current project is focused on the study of basic mechanisms of polarization of the innate immune response. Macrophages are the primary cell type responsible for the polarization of the innate immunity either by initiating and propagating inflammation (M1 phenotype) or resolving inflammation to promote tissue healing (M2 phenotype). A relative new idea is that the dysregulation of macrophage polarization with the prevalence of M1 over M2 phenotype promotes wide-spread inflammation and acute tissue injury. In the case of lungs acute lung injury (ALI) may evolve to acute respiratory distress syndrome (ARDS), a highly lethal form of respiratory failure. Hence, understanding the mechanisms by which macrophages polarize into functionally distinct phenotypes may lead to new therapeutic strategies to prevent or treat ARDS. Nuclear factor κB (NFκB) is a master regulator of inflammation being responsible for the expression of genes that promote or resolve inflammation. While the p65/p50 configuration of NFκB promotes inflammation, the p50/p50 configuration promotes resolution. We reason that these configurations also regulate how macrophages polarize into distinct phenotypes. In this regard, we recently discovered that suppressor of cytokine signaling-1 (SOCS1) may operate the switch in NFκB function since it targets nuclear p65 but not p50 to degradation changing the relative abundances of these component subunits in the nucleus. The finding that SOCS1 is sensitive to inhibition by nitric oxide (NO) and possibly other reactive species also indicate novel molecular mechanisms by which SOCS1 activity, NFκB function, pro- and anti-inflammatory transcription, as well as macrophage polarization and inflammatory outcomes are regulated. These mechanisms are the focus of our three proposed aims: (1) to determine the mechanism by which SOCS1 promotes NFκB functional switch from that of a pro- to that of an anti-inflammatory transcriptional complex; (2) to determine if changes in the intracellular redox state of macrophages affects SOCS1 activity and NFκB function as a transcription factor and (3) Determine how SOCS1 expression in different immune cell types regulates the transition between inflammation propagation and resolution in a mouse model of bacterial pneumonia.