Fractalkine (CX3CL1), a new factor protecting beta-cells against TNFalpha

Rutti, Sabine and Arous, Caroline and Schvartz, Domitille and Timper, Katharina and Sanchez, Jean-Charles and Dermitzakis, Emmanouil and Donath, Marc Y. and Halban, Philippe A. and Bouzakri, Karim. (2014) Fractalkine (CX3CL1), a new factor protecting beta-cells against TNFalpha. Molecular Metabolism, 3 (7). pp. 731-741.

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Official URL: https://edoc.unibas.ch/61702/

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We have previously shown the existence of a muscle-pancreas intercommunication axis in which CX3CL1 (fractalkine), a CX3C chemokine produced by skeletal muscle cells, could be implicated. It has recently been shown that the fractalkine system modulates murine beta-cell function. However, the impact of CX3CL1 on human islet cells especially regarding a protective role against cytokine-induced apoptosis remains to be investigated. Gene expression was determined using RNA sequencing in human islets, sorted beta- and non-beta-cells. Glucose-stimulated insulin secretion (GSIS) and glucagon secretion from human islets was measured following 24 h exposure to 1-50 ng/ml CX3CL1. GSIS and specific protein phosphorylation were measured in rat sorted beta-cells exposed to CX3CL1 for 48 h alone or in the presence of TNFalpha (20 ng/ml). Rat and human beta-cell apoptosis (TUNEL) and rat beta-cell proliferation (BrdU incorporation) were assessed after 24 h treatment with increasing concentrations of CX3CL1. Both CX3CL1 and its receptor CX3CR1 are expressed in human islets. However, CX3CL1 is more expressed in non-beta-cells than in beta-cells while its receptor is more expressed in beta-cells. CX3CL1 decreased human (but not rat) beta-cell apoptosis. CX3CL1 inhibited human islet glucagon secretion stimulated by low glucose but did not impact human islet and rat sorted beta-cell GSIS. However, CX3CL1 completely prevented the adverse effect of TNFalpha on GSIS and on molecular mechanisms involved in insulin granule trafficking by restoring the phosphorylation (Akt, AS160, paxillin) and expression (IRS2, ICAM-1, Sorcin, PCSK1) of key proteins involved in these processes. We demonstrate for the first time that human islets express and secrete CX3CL1 and CX3CL1 impacts them by decreasing glucagon secretion without affecting insulin secretion. Moreover, CX3CL1 decreases basal apoptosis of human beta-cells. We further demonstrate that CX3CL1 protects beta-cells from the adverse effects of TNFalpha on their function by restoring the expression and phosphorylation of key proteins of the insulin secretion pathway.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Diabetes Research (Donath)
UniBasel Contributors:Donath, Marc Y.
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:21 Jul 2020 15:34
Deposited On:21 Jul 2020 15:34

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