Cyclic adenosine monophosphate–responsive element modulator alpha overexpression impairs function of hepatic myeloid‐derived suppressor cells and aggravates immune‐mediated hepatitis in mice

Abstract

Molecular factors driving immune-mediated inflammation in the liver are incompletely understood. The transcription factor, cyclic adenosine monophosphate-responsive element modulator alpha (CREMa) 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 CREMa in liver disease, we subjected transgenic (Tg) mice overexpressing CREMa 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 CREMa 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, CREMa overexpression did not induce a predominant Th17 response in intrahepatic T cells, given that hepatic crem tg CD4 1 T cells expressed less interleukin (IL)-17 than wt T cells. Reconstitution of Rag1 2/2 mice with Crem 2/2 T cells did not ameliorate ConA hepatitis. Overexpression of CREMa did not influence NK and NKT-cell effector functions either. Interestingly, a subset of monocytic myeloid-derived suppressor cells (MDSCs) also expressed CD2 and CREMa. 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 CREMa in hepatic monocytic MDSCs for the pathogenesis of immune-mediated liver disease. (HEPATOLOGY 2015;61:990-1002) A utoimmune hepatitis (AIH) has a wide spectrum of clinical presentations, ranging from asymptomatic disease, acute or chronic hepatitis, to fulminant hepatic failure, and is characterized by intrahepatic lymphocyte activation, interface hepatitis, circulating autoantibodies, hypergammaglobulinemia, and a favorable response to immunosuppression. 1In concordance with other autoimmune diseases, AIH is associated with non-organ-specific antibodies (Abs), such as antinuclear Abs, in the context of hepatic

The Immunobiology of Receptor Activator for Nuclear Factor Kappa B Ligand and Myeloid‐Derived Suppressor Cell Activation in Immunoglobulin G4–Related Sclerosing Cholangitis

“…Our data demonstrate an increase of CD11b + CD33 + HLA-DR −/lo MDSCs and the receptor RANK in the periphery of IgG4-SC. This is consistent with other reports in immune-mediated diseases (12,40,41) that in response to chronic stimulation MDSC expansion was initiated and converted into immune-suppressive cells. RANKL induces the expansion and suppressive activity of MDSCs through interacting with RANK and activating the NF-κB pathway.…”

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

“…Since we observed major differences in the effect of CREMα Tg T cells on the Nemo Δhepa phenotype, associated with their differentiation pattern, 17 we further investigated the Th17 phenotype in hepatic T cells ( figure 6 B). Indeed, our FACS analysis revealed that CREMα Tg control mice showed no increase in Rorγt + T cells in the liver.…”

“…The expression of CREMα under control of the CD2 promoter in mice has been shown to reduce the number and alter the composition of immune cells in the liver. 17 Previous work in our laboratory 34 has shown the beneficial effects of depleting NK and NKT cells in Nemo Δhepa mice. In the same line of results, Nemo Δhepa /CREMα Tg animals display reduced amounts of NKT cells, and of proinflammatory macrophages, granulocytes, CD11b + DCs and CD8 + T cells, suggesting an overall reduced inflammatory response.…”

Non-canonical HIF-1 stabilization is essential for intestinal tumorigenesis

“…Small intestine, blood, bone marrow, and spleen cells were subjected to red blood cell lysis using Pharm Lyse (BD Biosciences, San Jose, USA). Flow cytometric analysis was done as described in detail before (79). Antibodies were purchased from eBioscience (CD45, CD11b, Ly6G, F4/80, CD3, CD4, CD8, CD103, and NK1.1), BD Biosciences (Gr1, I-A b ), and Biolegend (CD11c).…”