title: Fractalkine (CX3CL1), a new factor protecting β-cells against TNFα.
abstract: OBJECTIVE
  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 β-cell function. However, the impact of CX3CL1 on human islet cells especially regarding a protective role against cytokine-induced apoptosis remains to be investigated.
  
  
  METHODS
  Gene expression was determined using RNA sequencing in human islets, sorted β- and non-β-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 β-cells exposed to CX3CL1 for 48 h alone or in the presence of TNFα (20 ng/ml). Rat and human β-cell apoptosis (TUNEL) and rat β-cell proliferation (BrdU incorporation) were assessed after 24 h treatment with increasing concentrations of CX3CL1.
  
  
  RESULTS
  Both CX3CL1 and its receptor CX3CR1 are expressed in human islets. However, CX3CL1 is more expressed in non-β-cells than in β-cells while its receptor is more expressed in β-cells. CX3CL1 decreased human (but not rat) β-cell apoptosis. CX3CL1 inhibited human islet glucagon secretion stimulated by low glucose but did not impact human islet and rat sorted β-cell GSIS. However, CX3CL1 completely prevented the adverse effect of TNFα 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.
  
  
  CONCLUSIONS
  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 β-cells. We further demonstrate that CX3CL1 protects β-cells from the adverse effects of TNFα on their function by restoring the expression and phosphorylation of key proteins of the insulin secretion pathway.
authors.affiliation: Department of Genetic Medicine and Development, Geneva University, Geneva, Switzerland.
authors.forename: Sabine
authors.initials: S
authors.lastname: Rutti
authors.affiliation: Department of Genetic Medicine and Development, Geneva University, Geneva, Switzerland.
authors.forename: Caroline
authors.initials: C
authors.lastname: Arous
authors.affiliation: Department of Human Protein Sciences, Geneva University, Geneva, Switzerland.
authors.forename: Domitille
authors.initials: D
authors.lastname: Schvartz
authors.affiliation: Clinic of Endocrinology, Diabetes & Metabolism, University Hospital, Basel, Switzerland.
authors.forename: Katharina
authors.initials: K
authors.lastname: Timper
authors.affiliation: Department of Human Protein Sciences, Geneva University, Geneva, Switzerland.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Sanchez
authors.affiliation: Department of Genetic Medicine and Development, Geneva University, Geneva, Switzerland.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Dermitzakis
authors.affiliation: Clinic of Endocrinology, Diabetes & Metabolism, University Hospital, Basel, Switzerland.
authors.forename: Marc Y
authors.initials: MY
authors.lastname: Donath
authors.affiliation: Department of Genetic Medicine and Development, Geneva University, Geneva, Switzerland.
authors.forename: Philippe A
authors.initials: PA
authors.lastname: Halban
authors.affiliation: Department of Genetic Medicine and Development, Geneva University, Geneva, Switzerland.
authors.forename: Karim
authors.initials: K
authors.lastname: Bouzakri
keywords: Inflammation; Insulin secretion; Insulin signaling pathway; Islets; Myokines; Survival