Concentration and proteolysis of CX3CL1 may regulate the microglial response to CX3CL1.

Autor: Finneran D; Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, USA.; Department of Translational Neuroscience, Michigan State University, Grand Rapids, Michigan, USA., Li Q; Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, USA., Subbarayan MS; Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, USA.; Center for Excellence in Aging and Brain Repair, Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South Florida, Tampa, USA.; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, California, USA., Joly-Amado A; Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, USA., Kamath S; Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, USA., Dengler DG; Conrad Prebys Center for Chemical Genomics, Sandford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA., Gordon MN; Department of Translational Neuroscience, Michigan State University, Grand Rapids, Michigan, USA., Jackson MR; Conrad Prebys Center for Chemical Genomics, Sandford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA., Morgan D; Department of Translational Neuroscience, Michigan State University, Grand Rapids, Michigan, USA., Bickford PC; Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, USA.; Center for Excellence in Aging and Brain Repair, Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South Florida, Tampa, USA.; Research Service, James A Haley Veterans Hospital, Tampa, USA., Smith LH; Conrad Prebys Center for Chemical Genomics, Sandford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA., Nash KR; Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, USA.
Jazyk: angličtina
Zdroj: Glia [Glia] 2023 Feb; Vol. 71 (2), pp. 245-258. Date of Electronic Publication: 2022 Sep 15.
DOI: 10.1002/glia.24269
Abstrakt: Fractalkine (FKN) is a membrane-bound chemokine that can be cleaved by proteases such as ADAM 10, ADAM 17, and cathepsin S to generate soluble fragments. Studies using different forms of the soluble FKN yield conflicting results in vivo. These observations prompted us to investigate the function and pharmacology of two commonly used isoforms of FKN, a human full-length soluble FKN (sFKN), and a human chemokine domain only FKN (cdFKN). Both are prevalent in the literature and are often assumed to be functionally equivalent. We observed that recombinant sFKN and cdFKN exhibit similar potencies in a cell-based cAMP assay, but binding affinity for CX3CR1 was modestly different. There was a 10-fold difference in potency between sFKN and cdFKN when assessing their ability to stimulate β-arrestin recruitment. Interestingly, high concentrations of FKN, regardless of cleavage variant, were ineffective at reducing pro-inflammatory microglial activation and may induce a pro-inflammatory response. This effect was observed in mouse and rat primary microglial cells as well as microglial cell lines. The inflammatory response was exacerbated in aged microglia, which is known to exhibit age-related inflammatory phenotypes. We observed the same effects in Cx3cr1-/- primary microglia and therefore speculate that an alternative FKN receptor may exist. Collectively, these data provide greater insights into the function and pharmacology of these common FKN reagents, which may clarify conflicting reports and urge greater caution in the selection of FKN peptides for use in in vitro and in vivo studies and the interpretation of results obtained using these differing peptides.
(© 2022 Wiley Periodicals LLC.)
Databáze: MEDLINE
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