Heme oxygenase-1 activation in mononuclear phagocytes in acute Kawasaki disease.

Introduction: Kawasaki disease (KD) is an acute systemic vasculitis with an unknown etiology, and the underlying molecular mechanisms of vascular inflammation remain unclear. Mononuclear phagocyte activation is a prominent feature of the acute phase, but the upstream regulators of this process remain incompletely understood. This study aimed to investigate the role of heme oxygenase-1 in mononuclear phagocyte inflammation in KD. Methods: Integrating single-cell RNA sequencing (scRNA-Seq) and bulk RNA sequencing (bulk RNA-Seq) data, we analyzed differences in peripheral blood immune cell composition and key molecular expression profiles in children with KD to identify potential targets linked to mononuclear phagocyte activation. We collected clinical samples from KD patients to measure HMOX1 expression in peripheral blood mononuclear cells (PBMCs) and corresponding changes in serum inflammatory cytokines for validation. A KD mouse model was established via intraperitoneal injection of CAWS, and a separate therapeutic model was generated using SnMP. We then employed western blot, hematoxylin and eosin (HE) staining, cardiac ultrasound, and immunohistochemical staining to assess HMOX1 expression, coronary artery inflammatory infiltration, changes in coronary artery internal diameter, and macrophage infiltration. Results: Integrated analysis of single-cell and bulk RNA sequencing data showed elevated HMOX1 expression in mononuclear phagocytes from KD patients, correlating with reactive oxygen species and nuclear factor kappa B signaling pathways. In clinical samples, HMOX1 expression was increased in peripheral blood mononuclear cells, and serum tumor necrosis factor-alpha levels were elevated. In KD murine models, perivascular inflammatory infiltration, mononuclear phagocyte infiltration, and increased expression of HMOX1 in mononuclear phagocytes were observed, accompanied by elevated tumor necrosis factor-alpha expression. Notably, treatment with SnMP attenuated these pathological changes. Conclusions: Our study suggests that HMOX1 is upregulated in mononuclear phagocytes during acute Kawasaki disease and is associated with activation of inflammatory pathways. The HMOX1 inhibitor SnMP alleviated vascular inflammatory injury, indicating its potential as a therapeutic target for KD.