Endothelial cell pyroptosis plays an important role in Kawasaki disease via HMGB1/RAGE/cathespin B signaling pathway and NLRP3 inflammasome activation

Abstract

Kawasaki disease (KD) is the most common cause of pediatric cardiac disease in developed countries, and can lead to permanent coronary artery damage and long term sequelae such as coronary artery aneurysms. Given the prevalence and severity of KD, further research is warranted on its pathophysiology. It is known that endothelial cell damage and inflammation are two essential processes resulting in the coronary endothelial dysfunction in KD. However, detailed mechanisms are largely unknown. In this study, we investigated the role of pyroptosis in the setting of KD, and hypothesized that pyroptosis may play a central role in its pathophysiology. In vivo experiments of patients with KD demonstrated that serum levels of pyroptosis-related proteins, including ASC, caspase-1, IL-1β, IL-18, GSDMD and lactic dehydrogenase (LDH), were significantly increased in KD compared with healthy controls (HCs). Moreover, western blot analysis showed that the expression of GSDMD and mature IL-1β was notably elevated in KD sera. In vitro, exposure of human umbilical vein endothelial cells (HUVECs) to KD sera-treated THP1 cells resulted in the activation of NLRP3 inflammasome and subsequent pyroptosis induction, as evidenced by elevated expression of caspase-1, GSDMD, cleaved p30 form of GSDMD, IL-1β and IL-18, and increased LDH release and TUNEL and propidium iodide (PI)-positive cells. Furthermore, our results showed that NLRP3-dependent endothelial cell pyroptosis was activated by HMGB1/RAGE/cathepsin B signaling. These findings were also recapitulated in a mouse model of KD induced by Candida albicans cell wall extracts (CAWS). Together, our findings suggest that endothelial cell pyroptosis may play a significant role in coronary endothelial damage in KD, providing novel evidence that further elucidates its pathophysiology.

Andrade-Oliveira Salvianolic Acid B Modulates Caspase-1–Mediated Pyroptosis in Renal Ischemia-Reperfusion Injury via Nrf2 Pathway

“…Besides, SalB significantly restored renal function in I/R mice and inhibited pyroptosis in both I/R and HK-2 cell models. Previous studies used the annexin V and propidium iodide double-positive stage and an LDH-release assay to confirm pyroptosis ( Liu W. et al, 2018 ; Jia et al, 2019 ); however, the specific cell morphology evidence of pyroptosis was lacking. Over recent years, different studies have recorded the morphology of the cells of pyroptosis by electron microscopy, despite pyroptosis occurring in different cells (HeLa cells ( Wang et al, 2017 ) and raw-asc cells), which all have the similar morphology of pyroptosis.…”

Extracellular HMGB1: a therapeutic target in severe pulmonary inflammation including COVID-19?

“…Recent observations demonstrate that RAGE provides a transport route for extracellular HMGB1 and HMGB1-partner molecule complexes by endocytosis to the endolysosomal compartment (Deng et al 2018;Porat et al 2018;Lin et al 2019;Yang et al 2019a;Jia et al 2019;Xu et al 2014;Yang et al 2016a) (Fig. 1).…”

The effects of baicalin on piglets challenged with Glaesserella parasuis

“…Previous research has shown that HMGB1 released from mouse trophoblasts contributes to inflammation during Brucella melitensis infection [ 38 ]. HMGB1 is reported to induce signalling via the RAGE receptor and the HMGB1/RAGE/cathepsin B signalling pathway, which activates NLRP3-dependent coronary endothelial cell pyroptosis and thus plays an important role in the endothelial damage that occurs in Kawasaki disease [ 39 ]. The HMGB1—RAGE proinflammatory axis promotes vascular inflammation and endothelial cell apoptosis, resulting in vascular injury during acute limb ischaemia and reperfusion [ 40 ].…”