CX3CL1/CX3CR1 signaling targets for the treatment of neurodegenerative diseases.

1. Pharmacol Ther. 2022 Mar;231:107989. doi: 10.1016/j.pharmthera.2021.107989. Epub 2021 Sep 4. CX3CL1/CX3CR1 signaling targets for the treatment of neurodegenerative diseases. Subbarayan MS(1), Joly-Amado A(2), Bickford PC(3), Nash KR(4). Author information: (1)Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa FL-33612, USA; Center for Excellence in Aging and Brain Repair, Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa FL-33612, USA. (2)Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa FL-33612, USA. (3)Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa FL-33612, USA; Center for Excellence in Aging and Brain Repair, Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa FL-33612, USA; Research Service, James A Haley Veterans Hospital, 13000 Bruce B Downs Blvd, Tampa FL-33612, USA. (4)Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa FL-33612, USA. Electronic address: nash@usf.edu. Neuroinflammation was initially thought of as a consequence of neurodegenerative disease pathology, but more recently it is becoming clear that it plays a significant role in the development and progression of disease. Thus, neuroinflammation is seen as a realistic and valuable therapeutic target for neurodegeneration. Neuroinflammation can be modulated by neuron-glial signaling through various soluble factors, and one such critical modulator is Fractalkine or C-X3-C Motif Chemokine Ligand 1 (CX3CL1). CX3CL1 is produced in neurons and is a unique chemokine that is initially translated as a transmembrane protein but can be proteolytically processed to generate a soluble chemokine. CX3CL1 has been shown to signal through its sole receptor CX3CR1, which is located on microglial cells within the central nervous system (CNS). Although both the membrane bound and soluble forms of CX3CL1 appear to interact with CX3CR1, they do seem to have different signaling capabilities. It is believed that the predominant function of CX3CL1 within the CNS is to reduce the proinflammatory response and many studies have shown neuroprotective effects. However, in some cases CX3CL1 appears to be promoting neurodegeneration. This review focusses on presenting a comprehensive overview of the complex nature of CX3CL1/CX3CR1 signaling in neurodegeneration and how it may present as a therapeutic in some neurodegenerative diseases but not others. The role of CX3CL1/CXCR1 is reviewed in the context of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), ischemia, retinopathies, spinal cord and neuropathic pain, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis, and epilepsy. Copyright © 2021 Elsevier Inc. All rights reserved. DOI: 10.1016/j.pharmthera.2021.107989 PMID: 34492237 [Indexed for MEDLINE] Conflict of interest statement: Declaration of Competing Interest KRN and PCB were issued the patent (#10815285) titled Recombinant adeno-associated virus-mediated expression of fractalkine for treatment of neuroinflammatory and neurodegenerative diseases. MSS and AJA declare that there are no conflicts of interest.