The degeneration of alveolar bone and inflammation of the periodontal ligament are hallmark manifestations of periodontitis [1]. Both human and animal studies have demonstrated a robust association between diabetes mellitus and the exacerbation of periodontal pathology [2,3]. Elevated concentrations of pro-inflammatory cytokines have been observed in the periodontal tissues of diabetic individuals. Diabetes is implicated in inducing intricate systemic metabolic alterations that adversely influence distant tissues, including the periodontal ligament [4]. Such metabolic perturbations could modulate local inflammatory responses, thereby rendering the periodontal ligament increasingly pro-inflammatory [5,6]. To date, limited empirical investigations have been conducted to elucidate the mechanisms by which diabetes potentiates inflammatory processes in human periodontal ligament cells (HPDLCs), which constitute the majority of the periodontal ligament.

In the context of diabetes mellitus, systemic low-grade inflammation is primarily precipitated by hyperglycemia [7]. Advanced glycation end products (AGEs), a complex amalgam of glucose, protein, or lipid molecules, are engendered via spontaneous non-enzymatic glycation in hyperglycemic milieus [8]. AGEs, functioning as damage-associated molecular patterns (DAMPs), elicit a modest inflammatory response by binding to the Receptor for AGE (RAGE) on the cell membrane and subsequently activating downstream inflammatory signaling cascades [9]. HPDLCs actively participate in periodontal inflammation through the secretion of cytokines and chemokines [10]. It has been ascertained that AGEs amplify endoplasmic reticulum stress-induced NF-κB pathways in HPDLCs, consequently augmenting the secretion of pro-inflammatory chemokines such as interleukin-6 (IL-6) and interleukin-8 (IL-8) [11]. Nucleotide-binding domain and leucine-rich repeat-containing (NOD-like) receptors (NLRs) constitute the primary family of pattern recognition receptors (PRRs) involved in discerning both pathogenic and endogenous stimuli, mediating inflammatory responses, and orchestrating the clearance of these stimuli [[12], [13], [14]]. Emerging evidence suggests that the NLRP3 inflammasome plays a pivotal role in chronic inflammation and in an array of diabetic complications [15]. Additional research is requisite to discern the influence of AGEs on macrophage NLRP3 inflammasome-mediated innate immune responses [16,17]. While ROS-NLRP3 signaling in response to AGEs is mediated by the RAGE/NF-κB pathway in human nucleus pulposus (NP) cells [16], it remains elusive whether NLRs contribute to the AGE-induced modest inflammatory response in HPDLCs. Further investigations are also needed to assess the potential exacerbation of inflammation by AGE pre-treatment in the presence of pathogen-associated molecular patterns (PAMPs) and to delineate the role of PRRs in this aggravation.

Consequently, the objective of the present study is to ascertain the interplay between the AGE-RAGE axis and NLRs in the AGE-induced inflammatory responses in HPDLCs. We further aim to explore whether AGE-primed activation of pro-inflammatory cytokines and NLRs can potentiate the inflammatory reaction instigated by muramyl dipeptide (MDP) in HPDLCs.