Interleukin-6 as an Oral–Vascular Inflammatory Bridge: Integrating CXCL10 and Haptoglobin 2-2 into a Potential Model of Periodontitis-Associated Cardiovascular Risk

Periodontitis is a chronic dysbiotic inflammatory disease increasingly recognized as a contributor to systemic inflammatory burden and cardiovascular risk. Consensus and mechanistic literature support an association between periodontitis and atherosclerotic cardiovascular disease, while recent interventional evidence suggests that intensive periodontal treatment can improve endothelial function, reduce systemic inflammation and oxidative stress, and favorably influence the progression of carotid intima-media thickness. Among candidate mediators, interleukin-6 (IL-6) is especially compelling because it participates in local periodontal inflammation, hepatic acute-phase activation, endothelial dysfunction, oxidative stress, and the biology of atherosclerotic cardiovascular disease. CXCL10 has emerged as a relevant adjunctive chemokine because it is detectable in saliva, serum, gingival crevicular fluid, and inflamed periodontal tissues. In addition, it has also been implicated in atherosclerosis and adverse cardiac remodeling. Proteogenomic evidence suggests that CXCL10 may act as a potential downstream mediator of IL-6-associated signaling in atherosclerosis. Haptoglobin 2-2 (Hp2-2), while not itself a primary cytokine driver, may function as a host-susceptibility modifier, as the Hp2-2 phenotype has been associated with impaired hemoglobin scavenging, HDL dysfunction, endothelial dysfunction, oxidative vulnerability, and higher cardiovascular risk, particularly in dysglycemic states. This review proposes an IL-6-centered model linking chronic periodontal inflammation to cardiovascular risk, with CXCL10 positioned as an inflammatory recruitment amplifier and Hp2-2 as a genotype-defined modifier of vascular susceptibility. The translational implications of this framework for precision oral–systemic risk assessment, integration of salivary and blood-based biomarkers, and future biomarker-guided intervention studies are discussed.