iRhom2 inhibits bile duct obstruction-induced liver fibrosis.

iRhom2 inhibits bile duct obstruction-induced liver fibrosis. Sci Signal. 2019 Oct 29;12(605): Authors: Sundaram B, Behnke K, Belancic A, Al-Salihi MA, Thabet Y, Polz R, Pellegrino R, Zhuang Y, Shinde PV, Xu HC, Vasilevska J, Longerich T, Herebian D, Mayatepek E, Bock HH, May P, Kordes C, Aghaeepour N, Mak TW, Keitel V, Häussinger D, Scheller J, Pandyra AA, Lang KS, Lang PA Abstract Chronic liver disease can induce prolonged activation of hepatic stellate cells, which may result in liver fibrosis. Inactive rhomboid protein 2 (iRhom2) is required for the maturation of A disintegrin and metalloprotease 17 (ADAM17, also called TACE), which is responsible for the cleavage of membrane-bound tumor necrosis factor-α (TNF-α) and its receptors (TNFRs). Here, using the murine bile duct ligation (BDL) model, we showed that the abundance of iRhom2 and activation of ADAM17 increased during liver fibrosis. Consistent with this, concentrations of ADAM17 substrates were increased in plasma samples from mice after BDL and in patients suffering from liver cirrhosis. We observed increased liver fibrosis, accelerated disease progression, and an increase in activated stellate cells after BDL in mice lacking iRhom2 (Rhbdf2-/- ) compared to that in controls. In vitro primary mouse hepatic stellate cells exhibited iRhom2-dependent shedding of the ADAM17 substrates TNFR1 and TNFR2. In vivo TNFR shedding after BDL also depended on iRhom2. Treatment of Rhbd...
Source: Science Signaling - Category: Biomedical Science Authors: Tags: Sci Signal Source Type: research