Abstract
Acute liver failure (ALF) is a rare but life-threatening systemic disorder. The innate immune regulation has an important role in this process; however, the specific mechanisms are not completely clear. Using the LPS + D-GalN-induced ALF mouse model, we found that the survival rate of PTPN14-deficient mice was higher than that of the control group, while the release of inflammatory factors was significantly lower. We further showed that PTPN14 interacted with SOCS7, and promoted the degradation of SOCS7 through ubiquitination at K11 and K48, thereby reducing the protein level of SOCS7 and weakening the inhibitory effects on inflammatory factors. More importantly, SOCS7 blocked the NF-κB signaling pathway by preventing the activity of the IKK complex, and then reduced the expression of downstream inflammatory factors. In this study, we firstly reported the inhibitory effect of SOCS7 on the NF-κB pathway in the ALF mouse model and elucidated the mechanism of PTPN14–SOCS7–NF-κB axis in the regulation of inflammation. These results provide new insights into the clinical treatment of ALF.
Highlights
Acute liver failure (ALF) is a rare but life-threatening critical illness, most commonly occurs in patients without preexisting liver disease[1]
Protein tyrosine phosphatase non-receptor type 14 (PTPN14)-deficient mice show lower inflammation in ALF In order to study the role of PTPN14 in ALF, the wildtype and PTPN14-deficient C57BL/6J mice were stimulated with LPS + D-GalN by intraperitoneal injection to construct an ALF model
The results showed that the expression and secretion of inflammatory factors were significantly reduced after PTPN14 knockout (Fig. 1e, f)
Summary
Acute liver failure (ALF) is a rare but life-threatening critical illness, most commonly occurs in patients without preexisting liver disease[1]. Cytokine storm has an important role in the pathogenesis of ALF. The large number of inflammatory cytokines released by the host will attack the liver, leading to severe tissue injury and liver failure[2]. In the face of uncontrolled cytokine storm, steroid treatment is still the main choice of clinical treatment. Studying the regulatory mechanisms from a perspective of the innate immune system and identifying key factors that trigger the uncontrolled inflammation, Protein tyrosine phosphatases (PTPs) are signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation[5]. A recent study indicated that PTPN14 mediated the dephosphorylation and restoration of vascular endothelial cadherin at adherens junctions in LPSinduced acute lung injury[9], suggesting that PTPN14 may have a role in the regulation of inflammation
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