Role of HMGB1 in an experimental model of Bacterial ligand induced Vasculitis

ABSTACT Kawasaki Disease (KD) is an acute febrile pediatric systemic vasculitis of unknown etiology and is the leading cause of acquired heart disease among children. Untreated children develop coronary artery aneurysms (CAAs) leading to cardiovascular abnormalities later in life. Intravenous immunoglobulin (IVIG) is the standard treatment, however up to 20% of patients are non-responsive to IVIG, with a higher risk of developing CAAs. Therefore, better understanding of KD pathogenesis is crucial for developing novel and more efficient therapies. High mobility group box 1 (HMGB1) is a pro-inflammatory mediator that is released primarily from activated leukocytes and platelets and activates NF-κB and the NLRP3 inflammasome via RAGE-dependent manner, releasing inflammatory cytokines such as IL-1β. Serum levels of HMGB1 are elevated during acute KD, and HMGB1 polymorphism is associated with CAA development in KD. Using the Lactobacillus casei cell wall extract (LCWE), a bacterial ligand-induced murine model of KD vasculitis, which mimics immunopathologic features of human KD, we have generated critical preliminary data on the contribution of HMGB1 in the development of the cardiovascular lesions of KD vasculitis. Our preliminary data show increased levels of HMGB1 in LCWE- induced WT KD mice, but diminished serum levels of HMGB1 in platelet-depleted mice following LCWE-induced KD vasculitis. In preliminary experiments, we observed that blocking HMGB1 with the anti-HMGB1 molecule (Glycyrrhizin) significantly improved KD vasculitis in this experimental model. However, the exact role of HMGB1 in the pathogenesis of KD vasculitis and the cellular sources of HMGB1 during KD vasculitis are unknown. Therefore, in this study, we aimed to explore the role and the cellular source of circulating HMGB1 in the LCWE-mediated murine KD vasculitis model. We hypothesize that HMGB1 plays an important role in the pathogenesis of KD vasculitis and that blocking the activity of HMGB1 may be beneficial in LCWE-induced KD vasculitis. Specific Aims: 1-) Determine the role of HMGB1 in LCWE-induced KD vasculitis, using anti-HMGB1 mAb and a peptide/protein inhibitor of HMGB1; Aim2-) Determine the role of HMGB1 in platelets and neutrophils in LCWE- induced KD vasculitis, using cell-specific HMGB1 knockout mice. If successful, our studies will reveal the contribution of HMGB1 in regulating innate immune response during LCWE-induced KD vasculitis, as well as potential novel biomarkers and therapeutic targets for KD.