Succinate Activation of SUCNR1 Connects Periodontitis to Neuroinflammation

Objectives: Periodontitis is a chronic inflammatory disease which may induce neuroinflammation, a well-recognized component of neurodegenerative diseases such as Alzheimer’s disease (AD). Diabetes is associated with both periodontitis and AD. We have shown that succinate elevates in diabetes and activates succinate receptor 1 (SUCNR1) to stimulate inflammation and osteoclastogenesis in vitro and in vivo. The objective of this study is to determine whether succinate/SUCNR1 signaling stimulates inflammation in periodontitis and enhances neuroinflammation.
Methods: Succinate levels were measured by metabolomics and the expression of SUCNR1 in gingival tissues and cells were determined by Immunofluorescence and in situ hybridization. We used ligature and Fusobacterium nucleatum inoculation to induce periodontitis in wild type (WT) and SUCNR1 knockout mice (KO). The morphology of microglia was examined by the size and form of the soma, and the presence and the length of secondary/tertiary branches. The inflammatory responses in the brain tissues from four groups of mice were compared by ELISA and qPCR. Primary microglia culture from WT and KO mice was conducted to assess the direct effects of succinate on microglial cells.
Results: Succinate levels significantly elevated in human gingival plaque of severe periodontitis patients and mouse serum. Ligature and F. nucleatum induced inflammation and alveolar bone loss in WT but not in KO mice. The levels of Iba-1, a microglial marker and morphological parameters suggested a significant stimulation of inflammation process in the brain tissue of WT with the induction of periodontitis but not in the KO mice. Succinate directly stimulated pro-inflammatory cytokines in WT primary microglia and the stimulation was significantly blunted in KO primary microglia.
Conclusions: Targeting SUCNR1 is a promising new strategy to suppress neuroinflammation with its direct action on microglia and indirect effects through reduced periodontitis and systemic inflammation.