Periodontitis Induces B Cell-Macrophage Crosstalk to Exacerbate Glucose Dysregulation in Obesity

A growing consensus indicates that periodontitis (PD) adversely affects glycemic control in type 2 diabetes, though its underlying mechanisms remain unclear. Here, we report that PD, induced by long-term oral ligatures, significantly aggravated hyperglycemia and hepatic gluconeogenesis in high-fat diet-induced obese mice, with its impact on insulin resistance being more pronounced in the liver than in adipose or muscle tissue. Immunologically, PD increased systemic B cell abundance, promoted hepatic B2 cell mobilization, facilitated the expansion of Kupffer cells and adipose tissue macrophages, and activated the NLRP3 inflammasome. Depleting B cells significantly alleviated PD-induced glucose dysregulation, whereas adoptive transfer of B cells from PD mice exacerbated glucose dysregulation and Kupffer cell expansion in Rag1^-/- mice. Mechanistically, upregulation of the interleukin (IL)-18 receptor was observed in PD-exposed B cells. IL-18 directly enhanced B cell proliferation, and hepatic macrophages from PD mice secreted elevated levels of IL-18, further driving B cell expansion. Neutralizing IL-18 or depleting macrophages significantly mitigated PD-associated metabolic and B cell abnormalities. Therefore, PD exacerbates hyperglycemia by promoting the pathogenic expansion of B cells and their crosstalk with macrophages via the IL-18 signaling axis. Targeting the NLRP3/IL-18 axis holds promise for preventing glucose dysregulation and aberrant immune cell interactions primed by PD.