IL-1 Signaling Is Critically Required in Stromal Cells in Kawasaki Disease Vasculitis Mouse Model

Abstract

Objective Kawasaki disease (KD) is the most common cause of acute vasculitis and acquired cardiac disease among US children. We have previously shown that both TLR2/MyD88 and IL-1β signaling are required for the Lactobacillus casei cell wall extract (LCWE)-induced KD vasculitis mouse model. The objectives of this study were to investigate the cellular origins of IL-1 production, the role of CD11c+ Dendritic Cells (DCs) and macrophages and the relative contribution of hematopoietic and stromal cells for IL-1 responsive cells, as well the MyD88 signaling in LCWE-induced KD mouse model of vasculitis. Approach and Results Using mouse knockout models as well as antibody depletion, we found that both IL-1α and IL-1β were required for LCWE-induced KD. Both DCs and macrophages were necessary and we found that MyD88 signaling was required in both hematopoietic and stromal cells. However, IL-1 response and signaling was critically required in non-endothelial stromal cells, but not hematopoietic cells. Conclusions Our results suggest that IL-1α and IL-1β as well as CD11c+ DCs and macrophages are essential for the development of KD vasculitis and coronary arteritis in this mouse model. Bone marrow chimera experiments suggest that MyD88 signaling is important in both hematopoietic and stromal cells, while IL-1 signaling and response is required only in stromal cells, but not in endothelial cells. Determining the role IL-1α and IL-1β and of specific cell types in the KD vasculitis mouse model may have important implications for the design of more targeted therapies and understanding of the molecular mechanisms of KD immunopathologies.

Role of Interleukin-1 Signaling in a Mouse Model of Kawasaki Disease–Associated Abdominal Aortic Aneurysm

“…For the first time, we demonstrate that in addition to Il1b , disruption of Il1a or the use of IL-1α neutralizing antibody significantly inhibited LCWE-induced AAA formation, highlighting the critical role played by IL-1α, in addition to IL-1β in AAA formation in this vasculitis model. Indeed, we have also recently shown the non-overlapping roles for IL-1α and IL-1β in LCWE-induced coronary arteritis lesions 57 . Supporting these experimental findings, serum IL-1α levels are significantly correlated with AAA severity in human patients and surgical endovascular repair decreased the IL-1α levels 60 , further suggesting a role of IL-1α in human AAA formation as well.…”

“…We have previously shown that the caspase-1/IL-1α and IL-1β pathways are important for the development of coronary arteritis and myocarditis in the LCWE-induced KD murine model 25, 57 . In the current study, we found that IL-1/IL-1R signaling and both IL-1 α and IL-1β are critical for the formation of AAA, suggesting that the development of cardiovascular lesions associated with KD in both coronary artery and systemic arteries, including for AAA, may share a similar pathophysiology through the NLPR3 inflammasome and the IL-1 signaling pathway.…”

Rationale and study design for a phase I/IIa trial of anakinra in children with Kawasaki disease and early coronary artery abnormalities (the ANAKID trial)

“…Studies in the LCWE-induced mouse model of KD vasculitis have shown that the NLRP3 inflammasome, caspase 1 activation and IL-1β and IL-1α are important in KD vasculitis (Rosenkranz, Schulte et al 2005, Lee, Schulte et al 2012, Lee, Wakita et al 2015). The IL-1 R antagonist, anakinra, which blocks both IL-1α and IL-1β, significantly blocked coronary arteritis, aortitis and myocarditis in this experimental model (Lee, Schulte et al 2012).…”

Kawasaki disease: etiopathogenesis and novel treatment strategies

“…Lee et al [51] showed the critical role of IL-1 in the pathogenesis of KD using mice knockout models and antibodies. This then led to clinical trials for the use of IL-1R (Anakinra) in children with KD and is currently in phase IIa of clinical trials [52].…”