Abstract 14614: Deleterious Effect of Interleukin-23/Interleukin-17 Axis and γδT Cells in Left Ventricular Remodeling After Myocardial Infarction
[Background] Adverse left ventricular (LV) remodeling after myocardial infarction (MI) is a major cause of heart failure. Myocardial necrosis releases or exposes normally sequestered antigenic constituents that trigger immune response. However, the question of which subsets of immune cells and inflammatory mediators modify the remodeling process remains unclarified. The present study aimed to determine the role of the IL-23/IL-17 axis in remodeling after MI.
[Methods and Results] (1) IL-23-/- and IL-17-/- mice were resistant to LV remodeling on day 28 after MI, as shown by preserved fractional shortening (FS) and shorter LV end-diastolic diameter (LVEDD). The expression levels of MMP-1, MMP-3 and MMP-9 were markedly suppressed in IL-23-/- and IL-17-/- mice. (2) Q-PCR analysis using sorted cells from infarcted hearts revealed that IL-23 was mainly produced from neutrophils and M1 macrophages, both of which were recruited on day 1 after MI, peaked at day 3, and decreased thereafter. (3) Intracellular cytokine staining revealed that IL-17-producing cells began to increase from day 3, peaked on day 7, and continued to be elevated at day 14. (4) IL-23 treatment up-regulated IL-17, IFN-γ, IL-22, and RORγt but had no effect on TNF-α, IL-6, IL-1β in cultured mononuclear cells isolated from both sham-operated and infarcted hearts. (5) IL-17-producing cells were almost completely abolished in IL-23-/- mice. (6) On day 7, IL-23-/- and IL-17-/- mice had significantly fewer neutrophils and γδT cells in the infarcted hearts than the wild-type mice. The number of infiltrating macrophages, dendritic cells, and NK/NKT cells was not significantly altered. CD4+ and CD8+ T cells were rather increased. (7) γδT cells were the major (≥90%) IL-17-producing cells in the infarcted hearts, while Th17 cells accounted for less than 10% of IL-17-producing cells. (8) TCRγδ-/- mice were resistant to LV remodeling after MI, as indicated by the better FS and shorter LVEDD.
[Conclusions] IL-23/IL-17 axis had a detrimental effect on remodeling after MI via the sustained recruitment of neutrophils and activation of MMPs. γδT cells are the main source of IL-17 in the infarcted hearts. Thus, IL-23/IL-17 axis and γδT cells are the potential therapeutic targets to mitigate remodeling after MI.
- © 2011 by American Heart Association, Inc.