Periodontitis is a prevalent global disease characterized by chronic inflammation, resulting in the destruction of periodontal tissues, including gingiva, periodontal ligament, cementum, and alveolar bone, ultimately leading to tooth loss [1]. Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder marked by elevated blood glucose levels, capable of causing long-term damage and impairment to various organs, including the nerves, eyes, kidneys, heart, and blood vessels. Diabetes mellitus increases the susceptibility of periodontal tissue to periodontitis pathogens, resulting in periodontitis as the sixth consequence of diabetes [2].

The innate immunity of the gingival epithelium serves as the primary defense against foreign infections in periodontal tissue. It is essential for the maintenance of a healthy periodontal tissue [3]. High glucose levels in diabetes mellitus can cause long-lasting low-grade chronic inflammation in periodontal tissue. Furthermore, the innate immune activity of gingival epithelial tissue may exhibit aberrations [4]. On one hand, the resistance of gingival epithelial tissue to periodontitis pathogens decreases in diabetic individuals. On the other hand, immune responses, activated by risk factors, lead to the synthesis of elevated levels of various inflammatory cytokines, subsequently resulting in severe alveolar bone resorption and premature tooth loss in individuals with diabetes [5]. Nevertheless, the mechanisms through which elevated glucose levels in diabetes mellitus induce aberrations in the innate immunity of gingival epithelial cells remain unclear. Macrophages are dynamic cells crucial for both initiating and resolving inflammation. They demonstrate a high degree of flexibility and heterogeneity, encompassing pro-inflammatory M1-like macrophages at one end and reparative M2-like macrophages at the other [6]. M1-like macrophages produce pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF, which upregulate destruction mediators in primary tissue and cause bone resorption [7]. In contrast, M2-like macrophages release anti-inflammatory cytokines like TGF-β and IL-10 to control inflammation and maintain immune system balance [8].

The endoplasmic reticulum (ER) primarily stores calcium within cells, transports lipids, metabolizes substances, and facilitates the creation and folding of proteins. ER stress (ERS) arises from the accumulation of misfolded or unfolded proteins in the ER lumen due to an augmented demand for protein folding [9]. The unfolded protein response (UPR) is activated in response to protein misfolding, regulating intracellular signaling to preserve protein homeostasis and endoplasmic reticulum functionality [10]. In mammalian cells, the UPR signaling cascade is initiated by three ER transmembrane sensors: inositol-requiring 1 (IRE1), double-stranded RNA-dependent protein kinase (PKR)-like ER kinase (PERK), and activating transcription factor 6 (ATF6) [11]. The IRE1 branch stands out as the most evolutionarily conserved signaling branch in the UPR, compared to branches characterized by other stress sensors. Through its endo ribonuclease (RNase) activity, activated IRE1α splices the mRNA encoding XBP1 to generate spliced XBP1 (XBP1-s), subsequently promoting the gene expression of UPR-associated regulators [12].

Additionally, the IRE1α pathway activates the NF-κB and MAPK signaling pathways, contributing to ROS accumulation during heightened ER stress [13]. Moreover, it modulates the polarization process of M1-M2 macrophages, influencing the resolution of regulated IRE1-dependent decay [14]. Although there has been progress in comprehending IRE1α signaling in inflammation, additional research is imperative to ascertain its regulatory role and molecular mechanisms in diabetic periodontitis.

The objective of this study was to examine the impact of inhibiting IRE1α on macrophage polarization in gingival tissues in experimental diabetic periodontitis through in vivo and ex vivo experiments. This investigation aims to offer novel insights and establish a theoretical basis for the treatment of type 2 diabetic periodontitis.