Cyclic Adenosine Monophosphate-Responsive Element Modulator Alpha Overexpression Impairs Function of Hepatic Myeloid-Derived Suppressor Cells and Aggravates Immune-Mediated Hepatitis in Mice

摘要

Molecular factors driving immune-mediated inflammation in the liver are incompletely understood. The transcription factor, cyclic adenosine monophosphate-responsive element modulator alpha (CREM) can endorse differentiation of T lymphocytes toward T-helper (Th)17 cells, thereby promoting autoimmunity in systemic lupus erythematosus or lung inflammation. To investigate the role of CREM in liver disease, we subjected transgenic (Tg) mice overexpressing CREM under control of the CD2 promoter (crem(tg) mice), which restrains expression mainly to lymphocytes (T, natural killer [NK], and NKT cells), to acute and chronic liver injury models. Already in steady state, Tg CREM overexpression broadly reduced hepatic immune cell numbers by decreasing their viability, but did not affect immune cell migration or the fibrogenic response to chronic liver injury. Strikingly, crem(tg) mice developed more severe immune-mediated hepatitis with a higher mortality rate, compared to wild-type (wt) mice, upon concanavalin A (ConA) administration. Unlike in T cells from spleen, CREM overexpression did not induce a predominant Th17 response in intrahepatic T cells, given that hepatic crem(tg) CD4(+) T cells expressed less interleukin (IL)-17 than wt T cells. Reconstitution of Rag1(-/-) mice with Crem(-/-) T cells did not ameliorate ConA hepatitis. Overexpression of CREM did not influence NK and NKT-cell effector functions either. Interestingly, a subset of monocytic myeloid-derived suppressor cells (MDSCs) also expressed CD2 and CREM. Crem(tg) MDSCs isolated from liver expressed reduced inducible nitric oxide synthase and arginase 1 and displayed a reduced T-cell suppressive activity. The adoptive transfer of wt MDSCs was capable of reducing the fulminant immune-mediated liver damage in crem(tg) mice to wt level. Conclusion: These results suggest compartmental differences of T cell activation pathways between liver and other organs in autoimmunity and define a functional role of CREM in hepatic monocytic MDSCs for the pathogenesis of immune-mediated liver disease. (Hepatology 2015;61:990-1002)