The proinflammatory cytokine, interleukin-17A, augments mitochondrial function and neurite outgrowth of cultured adult sensory neurons derived from normal and diabetic rats

Abstract

BackgroundDiabetic neuropathy comprises dying back of nerve endings that reflects impairment in axonal plasticity and regenerative nerve growth. Metabolic changes in diabetes can lead to a dysregulation of hormonal mediators, such as cytokines, that may constrain distal nerve fiber growth. Interleukin-17 (IL-17A), a proinflammatory and neurotropic cytokine produced by T-cells, was significantly reduced in sciatic nerve of streptozotocin (STZ)-diabetic rats. Thus we studied the effect of IL-17A on the phenotype of sensory neurons derived from age matched control or type 1 diabetic rats. The aims were to determine the ability of IL-17A to enhance neurite outgrowth in cultured sensory neurons, investigate the signaling pathways activated by IL-17A, study the role of mitochondria and mechanistically link to neurite outgrowth. ResultsIL-17A (10ng/ml; p<0.05) significantly and dose-dependently increased total neurite outgrowth in cultures of adult dorsal root ganglia (DRG) sensory neurons derived from both control and streptozotocin (STZ)-diabetic rats. This enhancement was mediated by IL-17A-dependent activation of extracellular-regulated protein kinase (ERK) and phosphoinositide-3 kinase (PI-3K) signal transduction pathways. Pharmacological blockade of one of these activated pathways triggered complete inhibition of neurite outgrowth. IL-17A augmented mitochondrial bioenergetic function of sensory neurons derived from control or diabetic rats and this was also mediated via ERK or PI-3K. IL-17A-dependent elevation of bioenergetic function was associated with augmented expression of proteins of the mitochondrial electron transport system complexes. ConclusionsIL-17A enhanced axonal plasticity through activation of ERK and PI-3K pathways and was associated with augmented mitochondrial bioenergetic function in sensory neurons.