Dual-specificity phosphatase 10 alleviates severe acute pancreatitis via the dephosphorylation of TAK1.

Abstract

Severe acute pancreatitis (SAP) is a serious condition characterized by an intense systemic inflammatory response that can lead to persistent multiple organ failure and sepsis. Dual-specificity phosphatase 10 (DUSP10), has been implicated in immunity and inflammation; however, its involvement in SAP remains unclear. This study focuses on exploring the function and mechanism of DUSP10 in SAP. As a classical experimental model of SAP, L-arginine was used for in vitro and in vivo studies. A DUSP10 global knockout (KO) mice model and administration of adeno-associated virus with DUSP10 were used to further investigate the function of DUSP10 in SAP. Disulfiram and 5Z-7-ox, inhibitors of pyroptosis and TAK1, were applied to study the protective mechanism of DUSP10. We found downregulated expression of DUSP10 in in vitro and in vivo SAP models. Pancreatic damage was largely enhanced in DUSP10-/- mice and AR42J cells treated with shDUSP10, but was attenuated in mice and AR42J cells overexpressing DUSP10; the related lung and kidney damage, inflammatory response and oxidative stress paralleled these results. DUSP10 deficiency exacerbates pyroptosis during SAP, and inhibition of pyroptosis by DSF treatment protects against DUSP10 deficiency in aggravating SAP. Immunofluorescence and immunoprecipitation assays prove direct physical binding of DUSP10 to TAK1, and treatment with 5Z-7-ox reduced SAP severity in DUSP10-/- mice, showing that DUSP10 affected the dephosphorylation of the TAK1, and regulated the degree of pyroptosis by mediating the TAK1/JNK/p38 pathway. In conclusion, our study indicates that DUSP10 is a novel mediator of SAP and can inhibit pyroptosis via the dephosphorylation of TAK1.