Interleukin-1 Beta–Mediated Sex Differences in Kawasaki Disease Vasculitis Development and Response to Treatment

Abstract

Objective: Kawasaki disease (KD) is the leading cause of acute vasculitis and acquired heart disease in children in developed countries. Notably, KD is more prevalent in males than females. We previously established a key role for IL (interleukin)-1 signaling in KD pathogenesis, but whether this pathway underlies the sex-based difference in susceptibility is unknown. Approach and Results: The role of IL-1 signaling was investigated in the Lactobacillus casei cell wall extract-induced experimental mouse model of KD vasculitis. Five-week-old male and female mice were injected intraperitoneally with PBS, Lactobacillus casei cell wall extract, or a combination of Lactobacillus casei cell wall extract and the IL-1 receptor antagonist Anakinra. Aortitis, coronary arteritis inflammation score and abdominal aorta dilatation, and aneurysm development were assessed. mRNA-seq (messenger RNA sequencing) analysis was performed on abdominal aorta tissue. Publicly available human transcriptomics data from patients with KD was analyzed to identify sex differences and disease-associated genes. Male mice displayed enhanced aortitis and coronary arteritis as well as increased incidence and severity of abdominal aorta dilatation and aneurysm, recapitulating the increased incidence in males that is observed in human KD. Gene expression data from patients with KD and abdominal aorta tissue of Lactobacillus casei cell wall extract-injected mice showed enhanced Il1b expression and IL-1 signaling genes in males. Although the more severe IL-1β–mediated disease phenotype observed in male mice was ameliorated by Anakinra treatment, the milder disease phenotype in female mice failed to respond. Conclusions: IL-1β may play a central role in mediating sex-based differences in KD, with important implications for the use of anti–IL-1β therapies to treat male and female patients with KD.

Inhibition of IL-6 in the LCWE Mouse Model of Kawasaki Disease Inhibits Acute Phase Reactant Serum Amyloid A but Fails to Attenuate Vasculitis

“…The differentially expressed proteins (LCWE vs. PBS control) were then analyzed using IPA upstream regulator analysis (Figure 1C) and STRING database analysis of Gene Ontology (Figure 1D). IL-1b was amongst the top upstream regulators when ranked by Z-score, in line with previous investigations in this model (12)(13)(14)19), and our findings that anakinra treatment suppressed the LCWE-induced proteome changes. STRING analysis identified pathways involved in cellular morphogenesis and cytoskeletal organization (Figure 1D; Supplementary Table 1).…”

“…STAT3 can be activated by a range of cytokines and growth factors including IL-6, IFNg, TNFa, CSF2, CSF3, IL-10, TGF-b, VEGF and EGF. To determine the possible upstream regulators of STAT3 in the LCWE-induced mouse model of KD vasculitis, we utilized our previously published RNA-seq data (GSE141072) (19) from the abdominal aorta of mice treated with PBS, LCWE or LCWE and anakinra. We analyzed this dataset for the expression of Stat3 and the genes encoding the cytokines and growth factors listed above (Figure 3A).…”

“…The LCWE-induced murine model of KD vasculitis captures many of the features of human KD (18,19). Like human KD, the murine model develops a much more vigorous disease phenotype in young animals and a greater severity in males.…”

Kawasaki disease: pathophysiology and insights from mouse models

“…Similarly, IL-1 and NLRP3-related gene transcripts are upregulated in PBMCs from patients with acute Kawasaki disease and are decreased during the convalescent phase of the disease 59 , and an IL1B-gene-related signature is associated with acute phase disease and IVIG resistance 130 . Furthermore, a study has shown that differential expression of IL-1β and related signalling genes might have a role in mediating the sex-based differences seen in patients with Kawasaki disease 131 . In the LCWE mouse model of Kawasaki disease, the activation of caspase 1, IL-1α and IL-1β is key to the development of coronary arteritis, aneurysms, myocarditis and abdominal aorta aneurysms 127,128,132 .…”

MicroRNA-223 Regulates the Development of Cardiovascular Lesions in LCWE-Induced Murine Kawasaki Disease Vasculitis by Repressing the NLRP3 Inflammasome

“…Wild-type (WT) C57BL/6 and miR223 −/y (B6.Cg-Ptprc a Mir223 tm1Fcam /J) mice were purchased from Jackson Laboratories. For this study, we only used male animals, as LCWE injection induces more severe and more consistent coronary vasculitis lesions and abdominal aorta aneurysms in male than female mice (25,40). All animals were housed under specific pathogen-free conditions at the animal center of Cedars-Sinai Medical Center.…”