CCL28 ameliorates chronic liver damage associated with the recruitment of immunosuppressive IgA antibody-secreting cells in mice.

AIMS: CCL28 functions as a key chemoattractant for IgA antibody-secreting cells (IgA+ ASCs) and is crucial for maintaining mucosal immune defense. Recent research has revealed IgA+ ASCs with immunosuppressive activity in non-mucosal tissues under inflammatory conditions. Here, we explored the contribution of CCL28 to chronic liver damage caused by carbon tetrachloride (CCl4). MATERIALS AND METHODS: We administered CCl4 to wild-type and CCL28 knockout (CCL28 KO) mice to induce chronic liver damage. Liver damage, inflammation, fibrosis, and the expression of chemokines and immunosuppressive molecules were evaluated by histology, real-time PCR, ELISA, and flow cytometry. KEY FINDINGS: Chronic CCl4 treatment increased CCL28 expression in endothelial cells and macrophages of injured liver tissues. CCL28 KO mice exhibited higher serum ALT levels and more severe liver fibrosis than wild-type mice. They also showed diminished numbers of IgA+ ASCs in the livers. Liver-infiltrating IgA+ ASCs highly expressed the immunosuppressive molecules IL-10 and FasL, together with the CCL28 receptor CCR10. Furthermore, activated hepatic stellate cells (HSCs), which primarily produce extracellular matrix proteins, were increased in the livers of CCL28 KO mice, while apoptotic HSCs were decreased. In vitro, B220+ cells containing immunosuppressive IgA+ ASCs enhanced HSC cytotoxicity, and this effect was attenuated by anti-FasL antibody. Consistent with these findings, anti-IL-10 receptor and anti-FasL antibody treatment exacerbated chronic liver damage and fibrosis in vivo. SIGNIFICANCE: These results demonstrate that CCL28 contributes to liver protection against chronic damage in association with the selective infiltration of immunosuppressive IgA+ ASCs.