Hyperglycemia Aggravates Periodontitis via Autophagy Impairment and ROS-Inflammasome-Mediated Macrophage Pyroptosis

Abstract

Macrophage pyroptosis drives the secretion of IL-1β, which has been recently reported to be a featured salivary biomarker for discriminating periodontitis in the presence of diabetes. This study aimed to explore whether macrophage pyroptosis plays a role in the development of diabetes mellitus–periodontitis, as well as potential therapeutic strategies. By establishing a model of experimental diabetes mellitus–periodontitis in rats, we found that IL-1β and gasdermin D were highly expressed, leading to aggravated destruction of periodontal tissue. MCC950, a potent and selective molecule inhibitor of the NLRP3 inflammasome, effectively inhibited macrophage pyroptosis and attenuated alveolar bone losses in diabetes mellitus–periodontitis. Consistently, in vitro, high glucose could induce macrophage pyroptosis and thus promoted IL-1β production in macrophages stimulated by lipopolysaccharide. In addition, autophagy blockade by high glucose via the mTOR-ULK1 pathway led to severe oxidative stress response in macrophages stimulated by lipopolysaccharide. Activation of autophagy by rapamycin, clearance of mitochondrial ROS by mitoTEMPO, and inhibition of inflammasome by MCC950 could significantly reduce macrophage pyroptosis and IL-1β secretion. Our study demonstrates that hyperglycemia promotes IL-1β production and pyroptosis in macrophages suffered by periodontal microbial stimuli. Modulation of autophagy activity and specific targeting of the ROS-inflammasome pathway may offer promising therapeutic strategies to alleviate diabetes mellitus–periodontitis.

AZGP1 Aggravates Macrophage M1 Polarization and Pyroptosis in Periodontitis

“…As 2 interconnected proinflammatory processes, macrophage M1 polarization and pyroptosis can activate adjacent immune cells and expand inflammatory reactions, which further aggravates tissue injury. In this study, we found that macrophage M1 polarization and pyroptosis were increased in periodontitis and T2DM-associated periodontitis, which is consistent with results from previous studies (Lam et al 2014; Li, Yin, et al 2019; Zhang et al 2021; Yuan et al 2022; Zhao et al 2023). Moreover, overexpression or knockout of Azgp1 promoted or attenuated macrophage M1 polarization and pyroptosis, accompanied by increased or inhibited activation of NF-κB and MAPK inflammatory pathways, respectively.…”

“…Specifically, M1 macrophages are characterized by the secretion of proinflammatory cytokines, such as interleukin (IL)–1β, IL-18, and tumor necrosis factor–α (TNF-α), among which premature IL-1β and IL-18 are cleaved by active caspase-1 and released during the process of pyroptosis (Zhang et al 2020; Han et al 2022). Notably, macrophage M1 polarization and pyroptosis have been found to be elevated in the periodontium of patients with periodontitis (Lam et al 2014; Yang et al 2018; Li, Yin, et al 2019; Yuan et al 2022), both of which were aggravated in the context of T2DM (Zhang et al 2021; Zhao et al 2023). However, how macrophage M1 polarization and pyroptosis are regulated in periodontitis and T2DM-associated periodontitis remains to be elucidated.…”

Immunomodulation by glucocorticoid-induced leucine zipper in macrophages: enhanced phagocytosis, protection from pyroptosis, and altered mitochondrial function

“…Ceramide-mediated regulation of mitochondrial ROS was observed to connect ROS, NLRP3caspase-1 inflammasome activation, and pyroptosis in cancer cells (78). Furthermore, scavenging mitochondrial ROS effectively mitigated pyroptosis and IL-1b secretion in the context of hyperglycemia-and periodontitis-related pyroptosis (79).…”

Multi-Omics Data Integration Reveals Key Variables Contributing to Subgingival Microbiome Dysbiosis-Induced Inflammatory Response in a Hyperglycemic Microenvironment

“…Reactive oxygen species (ROS) are known contributors to both periodontitis-and type 2 diabetes-induced inflammation [42]. Recently, it has been demonstrated that hyperglycemia exacerbates periodontitis in an ROS dependent manner [43] and that pregnant women with gestational diabetes have a higher level of oxidative markers in the saliva, gingival crevicular fluid and serum than healthy pregnant women [44]. Further work is thereby warranted to study the impacts of oxidative stress in our experimental cell culture model.…”