NPY Y1, IL-1RI, and Adrenergic Receptors Modulate P. gingivalis-Induced Inflammation

Periodontitis is a common polymicrobial inflammatory disease that can progress to severe tissue destruction and tooth loss. Porphyromonas gingivalis (P. gingivalis) is associated with periodontitis, and has been successfully used in experimental models to replicate the inflammation seen in clinical cases. Neuropeptide Y (NPY) and its Y1 receptor (Y1R) are present in the periodontium and may play a role in this inflammation by modulating norepinephrine, which, via β-adrenergic receptors (β-ARs), may modulate proinflammatory cytokines. Induction of cytokines, such as Interleukin-1β (IL-1β), can promote periodontitis-associated inflammation and precipitate the subsequent deleterious effects.

Objective: To determine whether manipulating the actions of NPY, norepinephrine, or IL-1β modulates proinflammatory cytokine gene expression during P. gingivalis-induced inflammation.

 

Methods: IL-1 Receptor Type I (IL-1RI) knockout mice or wild-type mice administered Y1R antagonist or α- and β -AR agonists and antagonists were injected with live P. gingivalis or vehicle into tissues over the calvaria. After 1 or 3 days, the tissues were processed for quantitative PCR and gene expression was determined for IL-1β, IL-6, and TNF-α. 

Results:  Gene expression of proinflammatory cytokines was potentiated with the blockade of Y1Rs or both central and peripheral β₂-ARs, while antagonizing peripheral β-ARs alone decreased expression. Agonizing α₁- or β₂-ARs, or antagonizing β₁-ARs resulted in decreased expression. Non-specifically antagonizing α-ARs also resulted in decreased expression pointing to a role for α₂-ARs in this inflammation model. 

Conclusion: Taken together these data suggest that during P. gingivalis-induced inflammation IL-1RI receptors are necessary for proinflammatory cytokine expression (IL-6 and TNF-α) and that the Y1Rs and ARs regulate proinflammatory gene expression with the central β₂-adrenergic receptors playing a critical role in this regulation. Since NPY, IL-1β, and norepinephrine have been implicated in the stress response, exploring these mechanisms will not only aid in identifying novel therapeutic targets, but elucidate the connection of stress to periodontitis.