Porphyromonas gingivalis inhibits M2 activation of macrophages by suppressing ‐ketoglutarate production in mice
Porphyromonas gingivalis inhibits M2 activation of macrophages by suppressing ‐ketoglutarate production in mice
复制标题
DOI：
10.1111/omi.12241
复制
发表时间：
2018-08
影响因子：
3.7
通讯作者：
S. Yu;L. Ding;D. Liang;L. Luo
中科院分区：
文献类型：
--
作者：
S. Yu;L. Ding;D. Liang;L. Luo
代谢途径的重编程在控制巨噬细胞极化成代谢疾病（如糖尿病）中的经典促炎M1或替代抗炎M2表型方面至关重要。牙龈卟啉单胞菌（Porphyromonasgingivalis）是牙周炎的重要致病菌，它可引起M1/M2活化失衡，从而形成促进牙周炎发病的高炎症环境。然而，牙龈卟啉单胞菌感染是否调节代谢途径以改变巨噬细胞极化仍不清楚。从6周龄雌性C57 BL/6小鼠收集骨髓来源的巨噬细胞（BMDM），并用牙龈卟啉单胞菌、牙龈卟啉单胞菌来源的LPS或IL-4刺激。通过实时定量PCR、RNA测序和蛋白质印迹法测定相对基因表达和蛋白质产生。还进行了比色测定，以评估α-酮戊二酸（α-KG）和琥珀酸的含量。牙龈卟啉单胞菌或牙龈卟啉单胞菌衍生的LPS诱导的炎症反应增强M1巨噬细胞和抑制M2巨噬细胞，即使在IL-4的存在下。牙龈卟啉单胞菌抑制Idh 1/2和Gpt 1/2 mRNA表达，增加Akgdh mRNA表达，从而降低α-KG/琥珀酸比值。补充细胞可渗透的二甲基-α-KG显著恢复了牙龈卟啉单胞菌感染期间的M2活化。我们的研究表明，牙龈卟啉单胞菌通过抑制M2巨噬细胞产生α-KG来维持高炎症状态。
Reprograming of metabolic pathways is critical in governing the polarization of macrophages into classical proinflammatory M1 or alternative anti-inflammatory M2 phenotypes in metabolic diseases, such as diabetes. Porphyromonas gingivalis, a keystone pathogen of periodontitis, causes an imbalance in M1/M2 activation, resulting in a hyperinflammatory environment that promotes the pathogenesis of periodontitis. However, whether P. gingivalis infection modulates metabolic pathways to alter macrophage polarization remains unclear. Bone-marrow-derived macrophages (BMDMs) were collected from 6-week-old female C57BL/6 mice and stimulated with P. gingivalis, P. gingivalis-derived LPS or IL-4. Relative gene expression and protein production were measured by quantitative real-time PCR, RNA sequencing and western blotting. Colorimetric assays were also performed to assess the amounts of α-ketoglutarate (α-KG) and succinate. P. gingivalis or P. gingivalis-derived LPS-induced inflammatory responses enhanced M1 macrophages and suppressed M2 macrophages, even in the presence of IL-4. P. gingivalis inhibited Idh1/2 and Gpt1/2 mRNA expression, and increased Akgdh mRNA expression, thus decreasing the ratio of α-KG/succinate. Supplementation of cell-permeable dimethyl-α-KG dramatically restored M2 activation during P. gingivalis infection. Our study suggests that P. gingivalis maintains a hyperinflammatory state by suppressing the production of α-KG by M2 macrophages.