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

Abstract

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)-β pathway genes influences both susceptibility to KD and coronary artery aneurysm (CAA) formation. TGF-β 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-β pathway, to characterize myofibroblasts, and to detect Tregs. Expression of proteins in the TGF-β 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 α-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 aneurismal 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-β 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.

Galectin-3 is a marker of myocardial and vascular fibrosis in Kawasaki disease patients with giant aneurysms

“…Genetic variants in TGF-β influence KD susceptibility and CAA formation [32]. TGF-β may contribute to coronary arteritis and aneurysm formation by promoting the generation of myofibroblasts from different cell lineages including endothelial cells and smooth muscle cells in media, fibroblasts in adventitia, and fibrocytes in the peripheral circulation [9], and expression of TGF-β pathway molecules in aneurysmal arterial walls 6. Proposed evolution of plasma Galectin-3 levels related to stages of Kawasaki Disease.…”

“…Immunofluorescent double-staining for α-SMA and Gal-3 were performed as previously described [9]. Binding of antibodies was detected following incubation with donkey anti-mouse IgG Alexa Fluor 488 (Jackson Immunoresearch laboratory, Cat.…”

“…We previously demonstrated α-SMA-expressing spindle-shaped cells with staining characteristics of myofibroblasts in the aneurysmal arterial wall of a KD patient [9]. To determine whether Gal-3 expressing cells also express α-SMA in the myocardium, we performed double staining for Gal-3 and α-SMA on the myocardium from the explanted heart of Case 3.…”

“…Galectin-3 (Gal-3) is a β-galactoside-binding lectin and a matricellular protein that plays a multifunctional role in inflammation, fibrosis, and cell differentiation [7] and is required for transforming growth factor (TGF)-β pathway-mediated myofibroblast activation [8] that is a key process in CAA formation in KD [9]. Gal-3 is expressed by fibroblasts [10] and inflammatory cells including monocytes/macrophages [11][12][13].…”

T lymphocytes and aortic aneurysms

“…The elevated production of myofibroblasts leads to enhanced recruitment of inflammation cells and damage to aortic walls, followed by aggravation of aneurysms. Therefore, TGF-β may contribute to the pathogenesis of KD, but cease the inflammation by eliciting Tregs [62]. IL-35, an emerging cytokines, is produced mainly by nTregs in CD4 + T cells [61].…”