The Fractalkine (FKN/CX3CL1) Pathway in Depression: A Critical Review of Its Role in Neuroinflammation and Therapeutic Potential.

Abstract

Major Depressive Disorder (MDD), a global psychiatric disorder, involves complex pathogenesis in which neuroinflammation is considered one of the core pathophysiological processes. The fractalkine (FKN, CX3CL1)/CX3CR1 signaling pathway, a critical mediator of neuron-microglia communication, has been implicated in neuroinflammation and comorbid models depression, yet its precise and dynamic role in MDD remains controversial and insufficiently understood. This review aims to critically synthesize the existing literature to address these gaps. We first analyze the evidence for neuroinflammation in MDD, involving glial cells and pro-inflammatory cytokines. We then focus on the dual and context-dependent roles of the FKN/CX3CR1 pathway in regulating microglial function, synaptic plasticity, and inflammatory responses. Through a comparative analysis of existing literature, we suggest that neuroinflammation is a significant driver in the onset and progression of MDD, potentially engaging immune cells like microglia and astrocytes, and triggering the discharge of pro-inflammatory factors. The FKN/CX3CR1 pathway may play a dual role in regulating microglial function, maintaining synaptic homeostasis, and mediating inflammatory responses. Its dysregulation is potentially closely associated with inflammatory responses and synaptic damage in comorbid models, such as depression with diabetes and depression with rheumatoid arthritis. However, its specific role in MDD has not been fully elucidated, and direct evidence linking this pathway to major depressive disorder remains limited, as most current findings are derived from comorbid models or preclinical studies rather than clinical investigations. This review will systematically explore the general role of neuroinflammation in MDD, dissect the mechanisms of the FKN/CX3CR1 pathway in neuroinflammation and existing depression models, and prospectively potential therapeutic strategies and future research directions based on this pathway, thereby attempting to provide a new theoretical basis for the precision diagnosis and treatment of MDD.