Liraglutide protects Rin-m5f beta cells by reducing procoagulant tissue factor activity and apoptosis prompted by microparticles under conditions mimicking instant blood-mediated inflammatory reaction.
Résumé
Instant Blood-Mediated Inflammatory Reaction (IBMIR) occurs at the vicinity of transplanted islets immediately after intraportal infusion and is characterized by cytokine secretion, tissue factor (TF) expression, and ss cell loss. Microparticles (MPs) are cellular effectors shed from the plasma membrane of apoptotic cells. Modulation of the properties of ss cell-derived MPs by liraglutide was assessed in a cellular model designed to mimic IBMIR oxidative and inflammatory conditions. Rin-m5f rat cells were stimulated by H2O2 or a combination of IL-1 and TNF-. Cell-derived MPs were applied to naive Rin-m5f for 24h. Apoptosis, MP release, TF activity, P-IB expression, and MP-mediated apoptosis were measured in target cells. Direct protection by liraglutide was shown by a significant decrease in the oxidative stress-induced apoptosis (18.7% vs. 7.6%, P<0.0001 at 1m liraglutide) and cellular TF activity (-40% at 100nm liraglutide). Indirect cytoprotection led to 20% reduction in MP generation, thereby lowering MP-mediated apoptosis (6.3% vs. 3.7%, P=0.022) and NF-B activation (-50%) in target cells. New cytoprotective effects of liraglutide were evidenced, limiting the expression of TF activity by ss cells and the generation of noxious MPs. Altogether, these data suggest that liraglutide could target pro-apoptotic and pro-inflammatory MPs in transplanted islets.