The IL-1β - BHLHE40 Axis in the Pathogenesis of Kawasaki Disease: Insights from Cell-Type-Specific Expression Analysis

Abstract

Kawasaki disease (KD) is an acute systemic vasculitis of unknown etiology that mainly affects infants and young children and can cause coronary artery dilatation or aneurysm formation. Although early treatment has improved outcomes, disease-specific biomarkers and the immune mechanisms that sustain vascular inflammation remain incompletely defined. Innate immune activation, particularly interleukin-1 (IL-1) signaling, has been implicated in KD pathogenesis, and microbial component-induced mouse models reproduce key features of KD-like coronary arteritis. BHLHE40 is an inflammation-associated transcription factor that regulates cytokines such as GM-CSF, IFN-{gamma}, and IL-10, suggesting a potential connection between IL-1 signaling and downstream effector programs in KD. In this study, we integrated publicly available single-cell and bulk transcriptomic datasets from human KD and LCWE-induced murine vasculitis. Human analyses included comparisons with healthy or febrile controls, whereas the mouse analyses evaluated vascular cell-type expression and the response to IL-1 receptor blockade. IL1B and BHLHE40 were increased in independent whole-blood KD cohorts, with modest but statistically significant positive correlations between their expression levels. Single-cell analysis showed that IL1B was concentrated in myeloid populations, whereas BHLHE40 was distributed across several immune populations, including NK and T cells. In LCWE-treated mice, vascular Bhlhe40 expression was reduced by Anakinra, and Il1b and Bhlhe40 were strongly correlated within the LCWE group.