Hyperglycaemia‐associated macrophage pyroptosis accelerates periodontal inflamm‐aging

Abstract

Aim: Pyroptosis and inflamm-aging have been newly identified to be involved in diabetic periodontitis. This study aimed to elucidate whether macrophage pyroptosis plays a role in periodontal inflamm-aging by impacting the senescence of fibroblasts, as well as the potential mechanism via NLR family CARD domain-containing protein 4 (NLRC4) phosphorylation.Materials and methods: Diabetes was induced in mice using streptozotocin. Periodontal pyroptosis and senescence were detected using immunohistochemical analysis. Prior to evaluating senescence in human gingival fibroblasts cultured with conditioned medium derived from macrophages, RAW 264.7 macrophages were confirmed to undergo pyroptosis by scanning electron microscopy and gasdermin D (GSDMD) detection. The NLRC4-related pathway was examined under hyperglycaemic conditions.Results: Our data showed that macrophage pyroptosis induced the expression of senescent markers in vivo and in vitro. Importantly, clearance of pyroptotic macrophages rescued senescence in fibroblasts. Furthermore, GSDMD activation and pyroptosis in hyperglycaemia were found to be mediated by NLRC4 phosphorylation.Conclusions: Hyperglycaemia could initially induce macrophage pyroptosis and lead to cellular senescence, thereby critically contributing to periodontal pathogenesis in diabetes. In particular, NLRC4 phosphorylation could be a potential therapeutic target for the inhibition of this process.

Pyroptosis in periodontitis: From the intricate interaction with apoptosis, NETosis, and necroptosis to the therapeutic prospects

“…(Nie et al, 2021) reported that hyperglycemia triggers gingival destruction and impairment of macrophage function, including inflammatory cytokine secretion, phagocytosis, chemotaxis, and immune responses (Nie et al, 2021). In line with this, (Zhao et al, 2021) also reported that hyperglycemia promotes GSDMDdependent pyroptosis of macrophages through NLRC4 phosphorylation, thus activating NF-kB signaling in HGFs and further aggravating periodontitis (Zhao et al, 2021). Diabetes also inhibits the proliferation and differentiation of osteoblasts in alveolar bone by activating the caspase-1/GSDMD/IL-1b pathway .…”

“…However, these results have not been verified in periodontitis. Pyroptosis was demonstrated to arise in human gingival fibroblasts (HGFs), macrophages, oral epithelial cells, human periodontal ligament fibroblasts (HPDLFs), human periodontal ligament stem cells (HPDLSCs), and osteoblasts during periodontitis ( Ziauddin et al., 2018 ; Zhuang et al., 2019 ; Chen et al., 2021 ; Lei et al., 2021 ; Li et al., 2021 ; Zhao et al., 2021 ). The human gingival epithelium (HGEs) is considered the first line of periodontal defense, protecting the periodontal tissue against various harmful pathogens.…”

“…Also, the pan-caspase inhibitor Z-VAD-FMK and the caspase-4 inhibitor Z-LEVD-FMK have been found to alleviate inflammation in PDLSCs exposed to P. gingivalis ( Chen et al., 2021 ). Knockdown of GSDMD has been found to alleviate P. gingivalis–related inflammation in HGFs ( Zhao et al., 2021 ). These results showed that pharmacological inhibition of canonical or noncanonical pyroptosis pathways or gene knockout of pyroptosis-associated molecules results in significantly reduced alveolar bone loss and periodontal tissue inflammation and damage.…”

Osteoporosis and Alveolar Bone Health in Periodontitis Niche: A Predisposing Factors-Centered Review

“…Second, macrophage-mediated inflammation and senescence are enhanced under hyperglycemic conditions, contributing to sustained inflammation status and aggravated periodontal damage [ 175 ]. Third, hyperglycemia-triggered macrophage pyroptosis associates with periodontal fibroblast senescence possibly via phosphorylation of NLR family CARD domain-containing protein 4 [ 176 ]. At last, immunocompromised macrophages in hyperglycemia bring about uncontrollable infection [ 177 ].…”

Periodontitis and Accelerated Biological Aging: A Geroscience Approach

“…Further, an abnormal accumulation of senescent cells in periodontal tissues has been proposed as a link between diabetes and periodontitis by Zhao et al (2021). Chronic hyperglycemia significantly increased the local burden of p16- and p21-positive cells in the gingival epithelium of diabetic mice, elevated the secretion of SASP factors (interleukin [IL]–1β, IL-6, and tumor necrosis factor–α) in gingival crevicular fluid (GCF), and accelerated inflammaging through inflammasome activation via NLR family CARD domain-containing protein 4 phosphorylation.…”