Insulin and IGF-1 have both overlapping and distinct effects on CD4+ T cell mitochondria, metabolism, and function

Abstract Insulin and insulin-like growth factor 1 (IGF-1) are metabolic hormones with known effects on CD4+ T cells through insulin receptor (IR) and IGF-1 receptor (IGF-1R) signaling. Here, we describe specific and distinct roles for these hormones and receptors. We have found that IGF-1R, but not IR, expression is increased following CD4+ T cell activation or following differentiation toward Th17 cells. Although both insulin and IGF-1 increase the metabolism of CD4+ T cells, insulin has a more potent effect. However, IGF-1 has a unique role and acts specifically on Th17 cells to increase IL-17 production and Th17 cell metabolism. Furthermore, IGF-1 decreases mitochondrial membrane potential and mitochondrial reactive oxygen species (mROS) in Th17 cells, providing a cytoprotective effect. Interestingly, both IR and IGF-1R are required for this effect of IGF-1 on mitochondria, which suggests that the hybrid IR/IGF-1R may be required for mediating the effect of IGF-1 on mitochondrial membrane potential and mROS production

Interleukin-17A Deficiency Accelerates Unstable Atherosclerotic Plaque Formation in Apolipoprotein E-Deficient Mice

Objective: Interleukin-17A (IL-17A), an inflammatory cytokine, has been implicated in atherosclerosis, in which inflammatory cells within atherosclerotic plaques express IL-17A. However, its role in the development of atheroscelrosis remains to be controversial. Methods and Results: To directly examine the role of IL-17A in atherosclerosis, we generated apolipoprotein E (ApoE)/IL-17A double-deficient (ApoE^[-/-]IL-17A^[-/-]) mice. Mice were fed with high-fat diet (HFD) for either 8 or 16 weeks, both starting at ages of 6-8 weeks. We found that splenic CD4+ T cells produced high amounts of IL-17A in ApoE^[-/-] mice after HFD feeding for 8 weeks. Atherosclerosis was significantly accelerated in HFD-fed ApoE^[-/-]IL-17A^[-/-] mice compared with ApoE^[-/-] mice. Splenic CD4+ T-cells of ApoE^[-/-]IL-17A^[-/-] mice after HFD feeding for 8 weeks, but not for 16 weeks, exhibited increased IFN-γ and decreased IL-5 production. Importantly, formation of vulnerable plaque as evidenced by reduced numbers of vascular smooth muscle cells and reduced type I collagen deposition in the plaque was detected in ApoE^[-/-]IL-17A^[-/-] mice after HFD feeding for 8 weeks. Conclusions: These results suggest that IL-17A regulates the early phase of atherosclerosis development after HFD feeding and plaque stability, at least partly if not all by modulating IFN-γ and IL-5 production from CD4+ T-cells