p75NTR alleviates diabetic periodontitis in mice by inhibiting inflammatory macrophage recruitment

Periodontitis is a common oral health condition that is closely related to systemic diseases such as diabetes.The p75 neurotrophin receptor (p75NTR) belongs to the tumor necrosis factor receptor superfamily members of the neurotrophic factor low affinity receptor, which can regulate various metabolic and inflammatory diseases by activating immune cells, including macrophages and monocytes. Additionally, it plays a regulatory role in inflammatory diseases related to diabetes. Maxillary tissue-derived macrophages are crucial components of the immune defense in periodontal tissues.The aim of this experiment was aimed at investigating the effects and potential mechanisms of p75NTR on macrophages in a murine model of diabetic periodontitis.

The p75NTR wild-type (WT) and knock-out (KO) mouse models of diabetic periodontitis were established through intraperitoneal injection of streptozotocin (STZ) 150 mg/kg combined with periodontal ligation. Twenty-four healthy male WT and KO mice were randomly selected and divided randomly into four groups (n = 6 per group): control group (group C), diabetes group (group D), periodontitis group (group P), diabetes + periodontitis group (group D + P).The destruction of periodontal tissues in mice with diabetic periodontitis was analyzed using Micro-CT and histological staining. The heterogeneity of macrophages in the maxillary tissue of WT and KO mice was assessed using single-cell RNA sequencing (scRNA-seq). Lastly, the expression levels of p65, macrophage markers F4/80, CCL3, IL-6, and TNF-α were examined by immunohistochemistry in the periodontal tissues of mice to determine if the alleviation of inflammation by p75NTR knockdown was associated with macrophages.

Micro-CT, histologic staining analysis showed: In the D + P group, the alveolar bone height and bone volume fraction were significantly greater in KO mice compared with WT mice, whereas the inflammation of periodontal tissues and bone-breaking activities were significantly lower in KO mice. scRNA-seq analysis revealed the heterogeneity of maxillary tissue macrophages in WT and KO mice, and down-regulated genes in maxillary tissue macrophages in KO mice were closely related to the regulation of inflammatory responses.Immunohistochemical analysis revealed that the positive expression of p65, macrophage markers F4/80, CCL3, IL-6, and TNF-α in the periodontal tissues of KO mice was markedly reduced compared to that of WT mice.

The p75NTR knockdown mitigates diabetic periodontitis by inhibiting the recruitment of inflammatory macrophages and the secretion of inflammatory factors.