PKM2⁺ apoptotic vesicle-mediated systemic senolytics ameliorate chronic periodontitis.

Abstract

Chronic periodontitis (CP) is one of the most prevalent local inflammatory disorders and is associated with various systemic diseases. However, the relationship between local CP pathogenesis and systemic metabolic responses is not fully elucidated. In this study, we show that CP causes systemic inflammation, leading to apoptotic resistance and senescent cell accumulation, which are crucial for maintaining local inflammation in a CP mouse model. Eliminating senescent cells through systemic senolytic therapy ameliorate local CP pathological changes. Proteomic analysis reveals that CP patient plasma extracellular vesicles show upregulation of immune response-related proteins and downregulation of metabolic and apoptosis-related proteins, among which pyruvate kinase M2 (PKM2) was significantly reduced. Moreover, CP mice show reduced circulating apoptotic vesicles (apoVs), particularly those carrying PKM2. Systemic administration of PKM2⁺ mesenchymal stem cell-derived apoVs (MSC-apoVs) effectively rescues apoptotic resistance, eliminates senescent cells, and mitigates CP phenotypes. Mechanistically, we show that chronic inflammation reduces the level of nuclear PKM2 to promote apoptotic resistance. Systemic infusion of PKM2⁺ MSC-apoVs facilitates the nuclear translocation of PKM2 to alleviate apoptotic resistance and eliminate senescent cells. Our findings suggest that elimination of senescent cells as a new strategy for CP treatment. In addition, we propose the concept that systemic metabolism may determine the maintenance of local inflammation pathogenesis in CP.