The Inhibition of Bruton Tyrosine Kinase Alleviates Acute Liver Failure via Downregulation of NLRP3 Inflammasome

Abstract

There is no effective treatment for acute liver failure (ALF) except for an artificial liver support system (ALSS) and liver transplant. Bruton tyrosine kinase (Btk) plays important immunoregulatory roles in the inflammatory diseases, but its possible function in ALF remains to be characterized. In this study, we detected the phosphorylation level of Btk in ALF mouse liver and analyzed the protective effects of Btk inhibitor on survival rate and liver damage in ALF mouse models. We measured the expression levels of various inflammatory cytokines in the ALF mouse liver and primary human monocytes. In addition, we examined the expression of the NLRP3 inflammasome in mouse models with or without Btk inhibition. Clinically, we observed the dynamic changes of Btk expression in PBMCs of ALSS-treated patients. Our results showed that Btk was upregulated significantly in the experimental ALF mouse models and that Btk inhibition alleviated liver injury and reduced the mortality in these models. The protective effect of Btk inhibitors on ALF mice partially depended on the suppression of NLRP3 inflammasome signaling. Clinical investigations revealed that the dynamic changes of Btk expression in PBMCs could predict the effect of ALSS treatment. Our work shows that Btk inhibition is an effective therapeutic strategy for ALF. Moreover, Btk is a useful indicator to predict the therapeutic effect of ALSS on liver failure, which might have great value in clinical practice.

In vivo Bruton’s tyrosine kinase inhibition attenuates alcohol-associated liver disease by regulating CD84-mediated granulopoiesis

“…Our data show that increased BTK phosphorylation is associated with increased liver inflammation. This is consistent with published reports showing increased BTK phosphorylation associated with exacerbated inflammation (12,20,26,32,36,50,51). Consistent with this, our results showed that, in vivo using BTKi treatment, myeloidspecific BTK-deficient mice or depletion of neutrophils with an anti-Ly6G antibody significantly reduced proinflammatory cytokines and chemokines in serum and liver.…”

“…Recent studies have shown BTK activation in mouse models of acute liver failure (50,51) and that inhibition reduced liver injury in warm ischemia-reperfusion in mice (34,51). Earlier, we reported the role of SYK, a member of the NTRKs, in hepatocytes and liver mononuclear cells in the pathogenesis of ALD and showed that in vivo SYK inhibitor administration can mitigate ALD in a mouse model, emphasizing the critical role of NTRK members in ALD (34).…”

“…BTK, a member of the Tec family kinases, is implicated in several acute, chronic, and auto-inflammatory diseases, including sterile liver inflammation, diabetic nephropathy, traumatic brain injury, sepsis, and systemic lupus erythematosus (12,19,22,23,26,31,32,35,38,50,51,59,60). Notably, BTK plays an essential role in neutrophil-mediated organ damage and inflammation (12,32,35,36).…”