Concentration and proteolysis of CX3CL1 may regulate the microglial response to CX3CL1.
CX3CL1
CX3CR1
Fractalkine
microglia
neuro-inflammation
Journal
Glia
ISSN: 1098-1136
Titre abrégé: Glia
Pays: United States
ID NLM: 8806785
Informations de publication
Date de publication:
02 2023
02 2023
Historique:
revised:
25
08
2022
received:
20
04
2022
accepted:
26
08
2022
pmc-release:
01
02
2024
pubmed:
16
9
2022
medline:
20
12
2022
entrez:
15
9
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 36106533
doi: 10.1002/glia.24269
pmc: PMC9772123
mid: NIHMS1833314
doi:
Substances chimiques
Chemokine CX3CL1
0
CX3C Chemokine Receptor 1
0
CX3CL1 protein, human
0
Cx3cl1 protein, mouse
0
Cx3cl1 protein, rat
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
245-258Subventions
Organisme : NIA NIH HHS
ID : R01 AG062557
Pays : United States
Organisme : NIA NIH HHS
ID : R21 AG055080
Pays : United States
Informations de copyright
© 2022 Wiley Periodicals LLC.
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