Abstract
The aim of this study was to evaluate the role of NLRP3 inflammasome on BU/CY-induced liver inflammation in mice after HSCT. HSCT mice model was established through infusion of 5 × 106 bone marrow mononuclear cells after conditioned with BU/CY. On day 7, 14, 21 and 28 after HSCT, mice were sacrificed for analysis of liver inflammation, cytokine secretion, NLRP3 expression and caspase-1 activation as well as release of ATP and high-mobility group protein B1 (HMGB1). Furthermore, NLRP3 selective inhibitor (BAY 11-7082) was administrated into mice after HSCT to evaluate its effects on liver inflammation. Severe liver inflammation and damage with elevated secretion of IL-1β and IL-18 were found in mice after HSCT. Meanwhile, elevated expressions of NLRP3 and caspase-1 activation in liver were found. In addition, increased release of ATP and HMGB1 were observed. Selective inhibition of NLRP3 decreased caspase-1 activation and secretion of IL-1β and IL-18. Furthermore, NLRP3 inhibition also reduced infiltration of macrophages and neutrophils and improved liver function. In conclusion, NLRP3 was involved in BU/CY-induced liver inflammation after HSCT and selectively inhibited it ameliorated liver inflammation and improved liver function, suggesting targeting NLRP3 might be a new approach in the prophylaxis of liver inflammation after HSCT.
Highlights
Liver sinusoid, abnormal liver function and subsequent occurrence of HVOD9
Given the regulation of inflammation of NLRP3, we aimed to evaluate its role in liver inflammation in mice after busulfan combined with cyclosphomide (BU/CY) + H SCT and showed NLRP3 inflammasome was associated with liver inflammation and subsequent liver damage
Selective inhibition of NLRP3 function ameliorated liver inflammation and improved liver function, suggesting therapeutically targeting NLRP3 inflammasome might be beneficial in the prophylaxis of liver injury after Hematopoietic stem cell transplantation (HSCT)
Summary
Inflammatory cell infiltrations into liver were observed, suggesting inflammation might be involved in the liver injury after HSCT. The exact mechanism of NLRP3 inflammasome assembly and subsequent activation is still not very clear and is believed that upon inflammatory stimulation, NLRP3 undergoes oligomerized, leading to recruitment of ASC through interaction of PYD, which activates pro-caspase-1 via interaction of an caspase recruitment domain (CARD) located within N-terminal of ASC13,14. Our previous study showed more severe liver inflammation, damage and higher occurrence of HVOD were observed in mice after BU/CY + HSCT than TBI + HSCT9. Given the regulation of inflammation of NLRP3, we aimed to evaluate its role in liver inflammation in mice after BU/CY + H SCT and showed NLRP3 inflammasome was associated with liver inflammation and subsequent liver damage. Selective inhibition of NLRP3 function ameliorated liver inflammation and improved liver function, suggesting therapeutically targeting NLRP3 inflammasome might be beneficial in the prophylaxis of liver injury after HSCT
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