CX3CR1 and CCR2: dynamic myeloid cell states across inflammatory diseases with implications for oral health and disease.

Chemokine receptor-mediated immune cell trafficking is a fundamental determinant of inflammatory disease outcomes. Among chemokine receptors, CCR2 and CX3CR1 represent two functionally distinct but interconnected axes that regulate inflammatory monocyte recruitment and tissue macrophage retention, respectively. However, emerging evidence suggests that these receptors function as dynamic regulators of context-dependent myeloid cell states rather than fixed markers of discrete immune cell subsets. A central focus of this review is the recruitment-to-residency axis, which describes the functional transition of myeloid cells from inflammatory recruitment to tissue adaptation during chronic inflammation. In acute inflammation, CCR2-dependent recruitment is often essential for host defense and tissue repair; however, sustained CCR2 signaling promotes chronic inflammation and tissue damage. Conversely, CX3CR1 signaling maintains homeostasis under steady-state conditions, but can contribute to disease chronicity by retaining pathogenic macrophage populations within tissues. In this review, we summarize the cellular sources and regulatory mechanisms of CX3CR1 and CCR2, discuss their context-dependent roles across neurological, cardiovascular, mucosal, metabolic, fibrotic, and infectious diseases, and propose a unifying recruitment-to-residency axis. We further discuss periodontitis as a representative chronic inflammatory disease in which dysregulated CCR2-CX3CR1 dynamics may contribute to persistent inflammatory macrophage accumulation and osteoclastogenic tissue destruction. Understanding the dynamic interplay between CX3CR1 and CCR2 provides a conceptual framework for precision immunomodulatory strategies targeting the transition points of chronic inflammatory diseases, including those affecting oral health.