Hepatic overexpression of cAMP-responsive element modulator α induces a regulatory T-cell response in a murine model of chronic liver disease.

Abstract

Th17 cells are a subset of CD4⁺ T-helper cells characterised by interleukin 17 (IL-17) production, a cytokine that plays a crucial role in inflammation-associated diseases. The cyclic AMP-responsive element modulator-α (CREMα) is a central mediator of T-cell pathogenesis, which contributes to increased IL-17 expression in patients with autoimmune disorders. Since an increased Th17 response is associated with a poor prognosis in patients with chronic liver injury, we investigated the relevance of Th17 cells for chronic liver disease (CLD) and hepatocarcinogenesis. Transgenic mice overexpressing CREMα were crossed with hepatocyte-specific Nemo knockout mice (Nemo^Δhepa) to generate Nemo^Δhepa/CREMα^Tg mice. The impact of CREMα^Tg on CLD progression was examined. Additionally, soft agar colony formation assays, in vitro studies, adoptive transfer of bone marrow-derived cells (BMDCs) and T cells, and gene arrays in T cells were performed. 8-week-old Nemo^Δhepa/CREMα^Tg mice presented significantly decreased transaminase levels, concomitant with reduced numbers of CD11b⁺ dendritic cells and CD8⁺ T cells. CREMα^Tg overexpression in Nemo^Δhepa mice was associated with significantly reduced hepatic fibrogenesis and carcinogenesis at 52 weeks. Interestingly, hepatic stellate cell-derived retinoic acid induced a regulatory T-cell (Treg) phenotype in CREMα^Tg hepatic T cells. Moreover, simultaneous adoptive transfer of BMDCs and T cells from CREMα^Tg into Nemo^Δhepa mice ameliorated markers of liver injury and hepatitis. Our results demonstrate that overexpression of CREMα in T cells changes the inflammatory milieu, attenuating initiation and progression of CLD. Unexpectedly, our study indicates that CREMα transgenic T cells shift chronic inflammation in Nemo^Δhepa livers towards a protective Treg response.