Fractalkine (CX3CL1), a new factor protecting β-cells against TNFα

Abstract

ObjectiveWe 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.MethodsGene 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.ResultsBoth 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.ConclusionsWe 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.

Chronic fractalkine administration improves glucose tolerance and pancreatic endocrine function

“…Compared with β cells, α cell K ATP channel conductance is much less (1%-10%) in the absence of glucose, and relatively less ATP is required to attenuate whole-cell K ATP currents in α cells than in β cells (21). Therefore, unlike in β cells, the basal membrane potential in α cells is already depolarized (about -40 mV) even at relatively low levels of intracellular ATP, as seen in islets (28). Consistent with this, we observed that FKN-Fc administration decreases plasma glucagon levels in mice ( Figure 1D).…”

“…FKN also potentiates GSIS in vitro in both mouse and human islets. Additionally, it has been shown that FKN treatment of human islets decreases glucagon release and protects against TNF-α-induced decreased GSIS (28). In this study, we used a long-acting FKN-Fc fusion protein to conduct chronic treatment studies in obese mice.…”

Circulating Follistatin Is Liver-Derived and Regulated by the Glucagon-to-Insulin Ratio

“…Cell death was measured by terminal deoxynucleotidyl transferase assay and proliferation was assessed by bromodeoxyuridine incorporation (26). Data are the mean of six experiments.…”

The skeleton in the closet: actin cytoskeletal remodeling in β-cell function

“…Physiological, integrinmediated cell-ECM communication is critical not only normal ␤-cell function and indeed survival, as discussed here, but also for insulin action on its target tissues. Pathological modification of the ECM in type 2 diabetes, for example by high-fat diet, hyperglycemia-induced advanced glycation end-products (AGEs), or inflammatory cytokine-induced fibrosis, has thus been shown to participate in the insulin resistance state of insulin-targeted tissues (muscle, adipose tissue, and liver) and could impair ␤-cell function in a similar fashion (4,50,59,107,138,146,147). Deleterious cytokines that are elevated in the circulation of individuals with type 2 diabetes directly affect the expression of proteins of different functional classes including the actin cytoskeleton in ␤-cells (103); perhaps this may also occur in target cells to modulate their insulin sensitivity.…”