Lane, M. E. | Search bioRxiv

bioRxiv2026

Spatial profiling of Kawasaki disease cardiac inflammation identifies STING as a therapeutic target

The cellular subsets and in situ mechanisms underlying the development of coronary arteritis in Kawasaki disease (KD), the leading cause of acquired heart disease in children, remain poorly defined. We characterized the cellular composition and spatial organization of cardiac inflammation in autopsy coronary artery (CA) specimens from KD patients using 64-plex immunofluorescence. We identified spatially organized immune infiltrates of neutrophils, macrophages, and T cells associated with arterial wall destruction and remodeling, as well as disrupted stromal/muscle cell colocalization and diffuse myocardial inflammation. Spatial analysis also revealed expression of the innate immune sensor STING in myeloid cells in KD CA tissues. Pharmacological and genetic inhibition of STING reduced vasculitis development in a mouse model of KD. These findings define the spatial immune architecture of KD cardiac inflammation, reveal inflammatory injury beyond the coronary arteries, and identify STING as a potential therapeutic target for treatment-resistant or severe KD.

immunology↗

bioRxiv2025

Sirtuin 1 Activation Mitigates Murine Vasculitis Severity by Promoting Autophagy and Mitophagy

BACKGROUNDSirtuin 1 (SIRT1), a NAD+-dependent protein deacetylase, regulates cardiovascular inflammation by modulating cellular stress, inhibiting NLRP3 activation, and promoting the clearance of damaged mitochondria. However, its precise role in the pathogenesis of Kawasaki disease (KD), a pediatric systemic vasculitis and the leading cause of acquired heart disease in children, remains unclear. METHODSUsing the Lactobacillus casei cell wall extract (LCWE) murine model of KD, we evaluated the severity of vasculitis in mice supplemented with NAD+ precursors, as well as transgenic mice overexpressing SIRT1, and mice with specific deletion of Sirt1 in vascular smooth muscle cells (VSMCs) and myeloid cells. Proteomics analysis was performed on the abdominal aortas of WT and SIRT1-overexpressing mice. We performed immunofluorescent staining of cardiovascular tissues to assess the expression of proteins related to the autophagy/mitophagy pathway and the pathogenic switch of VSMCs. Western blot analysis was performed on primary VSMCs and cardiovascular tissues to determine the impact of SIRT1 on autophagic flux. The production of pro-inflammatory cytokines was measured in bone marrow-derived macrophages and peritoneal lavage of transgenic mice using ELISAs. RESULTSSIRT1 expression was downregulated in cardiovascular lesions of LCWE-injected mice, which was associated with a significant reduction of circulating levels of nicotinamide. Supplementation of mice with NAD+ precursors or genetic overexpression of SIRT1 significantly reduced the development of LCWE-induced KD, while the specific deletion of Sirt1 in VSMCs or myeloid cells exacerbated vasculitis. Proteomics analysis indicated impaired mitophagy/autophagy and the pathogenic synthetic switch of VSMCs in LCWE-injected mice, which was rescued with SIRT1 overexpression and associated with reduced production of proinflammatory cytokines. CONCLUSIONSThis study reveals the presence of an impaired NAD+-SIRT1 axis in the pathogenesis of LCWE-induced KD vasculitis and the therapeutic potential of targeting this axis to reduce cardiovascular lesions and inflammation.

immunology↗