Porphyromonas gingivalis inhibits M2 activation of macrophages by suppressing -ketoglutarate production in mice

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 -ketoglutarate (-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 -KG/succinate. Supplementation of cell-permeable dimethyl--KG dramatically restored M2 activation during P.gingivalis infection. Our study suggests that P.gingivalis maintains a hyperinflammatory state by suppressing the production of -KG by M2 macrophages.