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.