Cyclic AMP is a key regulator of M1 to M2a phenotypic conversion of microglia in the presence of Th2 cytokines.
Cyclic AMP is a key regulator of M1 to M2a phenotypic conversion of microglia in the presence of Th2 cytokines.
复制标题
DOI：
10.1186/s12974-015-0463-9
复制
发表时间：
2016-01-13
影响因子：
9.3
通讯作者：
Pearse DD
中科院分区：
文献类型：
--
作者：
Ghosh M;Xu Y;Pearse DD
小胶质细胞和巨噬细胞在神经炎症中起核心作用。促炎细胞因子触发它们转化为经典活化（M1）表型，维持炎症并产生细胞毒性环境。相反，抗炎细胞因子使细胞朝向交替激活（M2）的组织修复表型。阐明参与M1至M2表型转换的信号转导途径可以提供对先天免疫应答如何在疾病或损伤的不同阶段被利用以介导神经保护和神经修复的见解。在存在促炎介质脂多糖（LPS）或肿瘤坏死因子-α（TNF-α）的情况下，对小胶质细胞（细胞系和原代）进行环磷酸腺苷（cAMP）和IL-4联合或单独给药。评估它们对M1和M2小胶质细胞特征性标志物表达的影响。类似地，当全身施用药剂时，在大鼠和小鼠的胸（T8）脊髓的挫伤性脊髓损伤（SCI）后，评价损伤部位内的小胶质细胞和巨噬细胞的M1和M2表型。已证明环AMP与IL-4协同作用以促进培养物中小胶质细胞的M1至M2转化。环AMP和IL-4的组合，但都不是单独的，诱导Arg-1+/iNOS−细胞表型，同时表达其他M2特异性标志物，包括TG 2和RELM-α。M2转化的小胶质细胞显示促炎细胞因子（TNF-α和IP-10）和活性氧的产生有所改善，吞噬特性无改变。M2 a的转化需要蛋白激酶A（PKA），但不需要由环AMP（EPAC）直接激活的交换蛋白。实验性SCI后，环AMP和IL-4的全身递送也促进了损伤中小胶质细胞和巨噬细胞群体动力学的显著M1至M2 a表型变化。使用初级小胶质细胞，小胶质细胞系，和CNS损伤的实验模型，我们证明，环AMP水平是一个关键的决定因素，在M1-M2极化。当小胶质细胞被促炎刺激和Th 2细胞因子激活时，高水平的环AMP促进Arg-1+ M2 a表型。Th 2细胞因子或cAMP独立地不促进这些变化。小胶质细胞的表型转化为改变多种神经系统疾病和损伤中细胞毒性小胶质细胞与修复性小胶质细胞的平衡提供了一种强有力的新治疗方法。
Microglia and macrophages play a central role in neuroinflammation. Pro-inflammatory cytokines trigger their conversion to a classically activated (M1) phenotype, sustaining inflammation and producing a cytotoxic environment. Conversely, anti-inflammatory cytokines polarize the cells towards an alternatively activated (M2), tissue reparative phenotype. Elucidation of the signal transduction pathways involved in M1 to M2 phenotypic conversion may provide insight into how the innate immune response can be harnessed during distinct phases of disease or injury to mediate neuroprotection and neurorepair. Microglial cells (cell line and primary) were subjected to combined cyclic adenosine monophosphate (cyclic AMP) and IL-4, or either alone, in the presence of pro-inflammatory mediators, lipopolysaccharide (LPS), or tumor necrosis factor-α (TNF-α). Their effects on the expression of characteristic markers for M1 and M2 microglia were assessed. Similarly, the M1 and M2 phenotypes of microglia and macrophages within the lesion site were then evaluated following a contusive spinal cord injury (SCI) to the thoracic (T8) spinal cord of rats and mice when the agents were administered systemically. It was demonstrated that cyclic AMP functions synergistically with IL-4 to promote M1 to M2 conversion of microglia in culture. The combination of cyclic AMP and IL-4, but neither alone, induced an Arg-1+/iNOS−cell phenotype with concomitant expression of other M2-specific markers including TG2 and RELM-α. M2-converted microglia showed ameliorated production of pro-inflammatory cytokines (TNF-α and IP-10) and reactive oxygen species, with no alteration in phagocytic properties. M2a conversion required protein kinase A (PKA), but not the exchange protein directly activated by cyclic AMP (EPAC). Systemic delivery of cyclic AMP and IL-4 after experimental SCI also promoted a significant M1 to M2a phenotypic change in microglia and macrophage population dynamics in the lesion. Using primary microglia, microglial cell lines, and experimental models of CNS injury, we demonstrate that cyclic AMP levels are a critical determinant in M1–M2 polarization. High levels of cyclic AMP promoted an Arg-1+ M2a phenotype when microglia were activated with pro-inflammatory stimuli and Th2 cytokines. Th2 cytokines or cyclic AMP independently did not promote these changes. Phenotypic conversion of microglia provides a powerful new therapeutic approach for altering the balance of cytotoxic to reparative microglia in a diversity of neurological diseases and injury.