The role of IL-6 in hyperlipidemia-induced accelerated rejection

Abstract

Hyperlipidemia induces accelerated rejection of cardiac allografts and resistance to tolerance induction using costimulatory molecule blockade in mice due in part to anti‐donor Th17 responses and reduced regulatory T cell function. Accelerated rejection in hyperlipidemic mice is also associated with increased serum levels of IL‐6. Here, we examined the role of IL‐6 in hyperlipidemia‐induced accelerated rejection and resistance to tolerance. Genetic ablation of IL‐6 prevented hyperlipidemia‐induced accelerated cardiac allograft rejection. Using Th17‐lineage fate tracking mice, we observed that IL‐6 is required to promote the development of anti‐donor Th17 lineage cells independently of antigen challenge. In contrast, the frequency of alloreactive T cells producing IL‐2 or IFN‐γ remained increased in hyperlipidemic IL‐6‐deficient mice. Ablation of IL‐6 overcame hyperlipidemia‐induced changes in Tregs, but was not sufficient to overcome resistance to costimulatory molecule blockade induced tolerance. We suggest that accelerated rejection in hyperlipidemic mice results from IL‐6 driven anti‐donor Th17 responses. While alterations in Tregs were overcome by ablation of IL‐6, the reversal of hyperlipidemia‐induced changes in Tregs was not sufficient to overcome increased Th1‐type anti‐donor T cell responses, suggesting that hyperlipidemia induced IL‐6‐independent effects on recipient immunity prevent tolerance induction.

T cell cholesterol transport is a metabolic checkpoint that links intestinal immune responses to dietary lipid absorption

“…Excess LDL can be incorporated to membranes of immune cells and further promotes immunopathology (72)(73)(74)(75)(76). In particular, enhanced Th17-associated inflammation has been observed in various genetic-and diet-induced models of hypercholesterolemia (77)(78)(79)(80)(81)(82). Recent studies have shown that vesicular-and non-vesicular cholesterol transport pathways converges at the PM (83,84).…”

IL-6 inhibition prevents costimulation blockade-resistant allograft rejection in T cell-depleted recipients by promoting intragraft immune regulation in mice

“…Consequently, several studies investigating IL-6 deficiency in autoimmunity 69 , but also in transplantation [70][71][72][73] have been reported. Besides ischemia-reperfusion injury and alloimmunity, hyperlipidemia was recently identified as a driver of IL-6 release in transplantation, causing Treg dysfunction and accelerated allograft rejection 74 . In clinical kidney transplantation, a team of investigators led by Vincenti assessed the potential benefit of IL-6 receptor blockade (using tocilizumab) in stable recipients (on CNIs) with subclinical inflammation in protocol biopsies.…”