Shedding light on the role of CX3CR1 in the pathogenesis of schizophrenia

Abstract

Schizophrenia has a complex and heterogeneous molecular and clinical picture. Over the years of research on this disease, many factors have been suggested to contribute to its pathogenesis. Recently, the inflammatory processes have gained particular interest in the context of schizophrenia due to the increasing evidence from epidemiological, clinical and experimental studies. Within the immunological component, special attention has been brought to chemokines and their receptors. Among them, CX3C chemokine receptor 1 (CX3CR1), which belongs to the family of seven-transmembrane G protein-coupled receptors, and its cognate ligand (CX3CL1) constitute a unique system in the central nervous system. In the view of regulation of the brain homeostasis through immune response, as well as control of microglia reactivity, the CX3CL1-CX3CR1 system may represent an attractive target for further research and schizophrenia treatment. In the review, we described the general characteristics of the CX3CL1-CX3CR1 axis and the involvement of this signaling pathway in the physiological processes whose disruptions are reported to participate in mechanisms underlying schizophrenia. Furthermore, based on the available clinical and experimental data, we presented a guide to understanding the implication of the CX3CL1-CX3CR1 dysfunctions in the course of schizophrenia.

Keywords: CX3CL1; CX3CR1; Schizophrenia.

Fig. 1

Scheme illustrating the structure, localization and signaling pathways affected by the CX3CL1–CX3CR1 axis. CX3CL1, produced mostly by neurons, is a membrane-bound molecule with a chemokine domain, mucin-like stalk, transmembrane region and cytoplasmic tail. Cleavage of CX3CL1 is mediated under physiological or pathological conditions by ADAM10 or ADAM17, MMP-2, MMP-3 and cathepsin S, respectively. Binding CX3CL1 to CX3CR1, which is a seven-transmembrane domain G_i protein-coupled receptor expressed primarily on microglia, results in an intracellular transmission engaging multiple signaling pathways. TM transmembrane domain, EL extracellular loop, IL intracellular loop

Fig. 2

The role of the CX3CL1–CX3CR1 signaling pathway in the pathology of schizophrenia. In physiological conditions, the interaction of CX3CL1 with CX3CR1 is essential for the regulation of multiple processes in the brain. The disturbances within this axis and subsequent disruptions within these mechanisms implicate the CX3CL1–CX3CR1 dyad in schizophrenia