The role of TGF-β and myofibroblasts in the arteritis of Kawasaki disease

Inflammation of medium-sized, muscular arteries and coronary artery aneurysms are hallmarks of Kawasaki disease (KD), an acute, self-limited vasculitis of children. We previously reported that genetic variation in transforming growth factor (TGF)-beta pathway genes influences both susceptibility to KD and coronary artery aneurysm (CAA) formation. TGF-beta signaling has been implicated in the generation of myofibroblasts that influence collagen lattice contraction, antigen presentation, and recruitment of inflammatory cells as well as the generation of regulatory T-cells (Tregs). These processes could be involved in aneurysm formation and recovery in KD. Coronary artery tissues from 8 KD patient autopsies were stained to detect proteins in the TGF-beta pathway, to characterize myofibroblasts, and to detect Tregs. Expression of proteins in the TGF-beta pathway was noted in infiltrating mononuclear cells and spindle-shaped cells in the thickened intima and adventitia. Coronary arteries from an infant who died on Illness Day 12 showed alpha-smooth muscle actin (SMA)-positive, smoothelin-negative myofibroblasts in the thickened intima that co-expressed IL-17 and IL-6. CD8+ T-cells expressing HLA-DR+ (marker of activation and proliferation) were detected in the aneurysmal arterial wall. Forkhead box P3 (FOXP3), whose expression is essential for Tregs, was also detected in the nucleus of infiltrating mononuclear cells, suggesting a role for Tregs in recovery from KD arteritis.TGF-beta may contribute to aneurysm formation by promoting the generation of myofibroblasts that mediate damage to the arterial wall through recruitment of pro-inflammatory cells. This multi-functional growth factor may also be involved in the induction of Tregs in KD. (c) 2013 Elsevier Inc. All rights reserved.