Lipidomics links oxidized phosphatidylcholines and coronary arteritis in Kawasaki disease

Abstract

Aims Coronary arteritis is a life-threatening complication that may arise in the acute stage of Kawasaki disease (KD), the leading cause of systemic vasculitis in childhood. Various microorganisms and molecular pathogens have been reported to cause KD. However, little is known about the key molecules that contribute to the development of coronary arteritis in KD. Methods and results To identify causative molecules for coronary arteritis in KD, we prospectively recruited 105 patients with KD and 65 disease controls in four different parts of Japan from 2015 to 2018. During this period, we conducted lipidomics analyses of their sera using liquid chromatography–mass spectrometry (LC-MS). The comprehensive LC-MS system detected a total of 27 776 molecules harbouring the unique retention time and m/z values. In the first cohort of 57 KD patients, we found that a fraction of these molecules showed enrichment patterns that varied with the sampling region and season. Among them, 28 molecules were recurrently identified in KD patients but not in controls. The second and third cohorts of 48 more patients with KD revealed that these molecules were correlated with inflammatory markers (leucocyte counts and C-reactive proteins) in the acute stage. Notably, two of these molecules (m/z values: 822.55 and 834.59) were significantly associated with the development of coronary arteritis in the acute stage of KD. Their fragmentation patterns in the tandem MS/MS analysis were consistent with those of oxidized phosphatidylcholines (PCs). Further LC-MS/MS analysis supported the concept that reactive oxygen species caused the non-selective oxidization of PCs in KD patients. In addition, the concentrations of LOX-1 ligand containing apolipoprotein B in the plasma of KD patients were significantly higher than in controls. Conclusion These data suggest that inflammatory signals activated by oxidized phospholipids are involved in the pathogenesis of coronary arteritis in KD. Because the present study recruited only Japanese patients, further examinations are required to determine whether oxidized PCs might be useful biomarkers for the development of coronary arteritis in broad populations of KD.

Resolution of Giant Coronary Aneurisms in a Child With Refractory Kawasaki Disease Treated With Anakinra

“…These data implicate the pathogenic role of atherogenic signals in KD. This suggests that the triggering of the innate response begins not only through the PAMPs or damage-associated molecular patterns (DAMPs) (26) but also from the activation of multiple pathways in a variety of cell types (27).…”

The up‐to‐date pathophysiology of Kawasaki disease

“…70,71 Oxidised phospholipids and LDLs, as DAMPs, modify the epigenetic status of monocytes and vascular cells, facilitate memory responses and boost inflammation. 72 Since oxidised phospholipids and LDLs are elevated during the acute phase of KD, 58 we hypothesise that such DAMPs may reprogramme the cellular metabolism and boost hyperinflammation of innate immune cells and vascular cells in patients with KD during its onset and recurrence. 67,68 Furthermore, the clinical and laboratory data have shown that serum IL-1b levels increase and IL-1 signalling is upregulated in KD.…”

“…107 In a subsequent high-resolution LC-MS-based lipidomic analysis, we confirmed that the KD-associated molecules possessed structures similar to those found in biofilm extracts from Y. pseudotuberculosis. 58…”

“…The lipid peroxidation products include malondialdehyde, 115 F2isoprostanes, 116 and oxidised phospholipids and LDLs. 58,117 Oxidised phospholipids evoke arterial wall inflammation in humans, 118 and oxidised LDLs induce pyroptosis in vascular endothelial cells. 119 Actually, blood levels of oxidised phosphatidylcholines 58 and oxidised LDLs 117 are associated with the development of coronary arteritis.…”

“…124 Using immobilised recombinant human LOX-1, various types of modified LDLs can be detected as LOX-1 ligands in patients with KD. 58 Therefore, LOX-1 ligand assay may better reflect the pathogenic activities of apolipoprotein B than the measurements of oxidised lipids or oxidised LDLs by LC-MS or monoclonal antibodies. LOX-1 ligand assay would be useful in the diagnosis of acute KD and possibly in the diagnosis of MIS-C fulfilling the diagnostic criteria for KD.…”