Apolipoprotein A4 regulates the immune response in carbon tetrachloride-induced chronic liver injury in mice.

This article explores the role of ApoA4 in a CCl-induced chronic liver injury (CLI) mouse model. C57BL/6J mice (WT) and ApoA4 knock-out (KO) mice were divided into CCl CLI (WT-CCl and KO-CCl) and olive oil solvent control groups (WT-Veh and KO-Veh). Some of the KO-CCl mice were additionally treated with recombinant mouse ApoA4 and primary mouse T lymphocyte injections. After 6 weeks, histological analyses, biochemical and superoxide dismutase (SOD) and malondialdehyde (MDA) assays, flow cytometry of immune cells and qRT-PCR analyses were performed. KO mice after treatment with CCl showed reduced hepatic SOD and enhanced serum MDA activities leading to worsening liver injury and fibrosis compared with WT-CCl, accompanied by enhanced hepatic alpha smooth muscle actin (α-SMA), tissue inhibitor of metalloproteinases-1 (TIMP-1) and collagen type I alpha 1 chain (COL1A1) transcriptions, elevated macrophage M1 levels, enhanced tumor necrosis factor-alpha (TNF-α), Interleukin 6 (IL-6) and C-C Motif Chemokine Ligand 5 (CCL5), but reduced Interleukin 10 (IL-10), monocyte chemotactic protein 1 (MCP-1), C-C Motif Chemokine Receptor 2 (CCR2), C-X3-C Motif Chemokine Receptor 1 (CX3CR1) and C-X-C Motif Chemokine Ligand 9 (CXCL9) transcription, as well as reduced CD3+, CD4+ and CD8+ T cell percentages in hepatic tissue, blood cells and spleen. In addition, CD11b+CD115+, CD11b+/Ly6C, CD11b+/LyC6 and CD11b+/Ly6C cells were enhanced, which partly reversed by ApoA4 protein and T cell injections. In conclusion, we propose that ApoA4 might be involved in liver protection via inhibiting fibrotic mediators and inflammatory cytokines, suppression of pro-inflammatory hepatic M1 cell invasion and regulation of CD8+ T and CD4+ T lymphocytes.