Ibone Labiano Ciriza. Gaixotasun Hepatikoen Taldea, Biodonostia OII.
Dra. María Jesús Perugorria y Dr. Jesús María Bañales.
Cholestatic liver diseases are characterised by a stopped or diminished bile flow and the accumulation of bile acids (BAs) and other toxic molecules within the liver. Cholestatic diseases can progress to advanced stages such as cirrhosis and hepatocellular carcinoma (HCC). The translocation of bacterial products from the gut to the liver is regarded as an important source of inflammatory signals promoting disease progression during cholestatic diseases and hepatocellular carcinogenesis. In the liver, bacterial products bind to Toll-like receptors (TLRs), thereby exacerbating inflammatory gene transcription. The triggering receptor expressed on myeloid cells 2 (TREM2) acts as a negative modulator of TLR-mediated signalling. In previous studies of the group, we have reported that this receptor plays a protective role upon acute and chronic hepatocellular damage. Therefore, in this project, we aimed to assess the role of TREM2 as a modulator of inflammatory responses during cholestasis and fibrosis-associated HCC. Our results reveal that TREM2 is upregulated in the liver of patients with cholestasis compared to control liver and this phenomenon is conserved in mice. Moreover, Trem2 deficient mice develop an exacerbated response to cholestasis in different mouse models of this condition, and Abx based treatment rescues some of the Trem2-associated effects in cholestasis. TREM2 also arises as a novel molecular mediator of the beneficial effects of UDCA in cholestasis, being UDCA an endogenous choleretic bile acid employed for the treatment of these diseases. In patients with HCC, TREM2 is most prominently expressed in tumour-associated macrophages and Trem2 deficient mice display exacerbated carcinogenesis in two models of fibrosis-associated HCC. Overall, TREM2 arises as a novel potential therapeutic target for the patients with cholestasis, and with HCC.
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