The functional characteristics CCNI modulation of myeloid- derived suppressor cells in liver inflammation

Abstract

There is increasing awareness of the immunologic roles of liver mononuclear populations including myeloid-derived suppressor cells (MDSCs). We took advantage of a large well defined cohort of 148 patients with liver inflammation and 45 health controls to focus on the qualitative and quantitative characteristics of MDSCs. We investigated the frequency, phenotype and functional capacities of MDSCs using peripheral blood MDSCs in a cohort of 55 patients with PBC, 40 with AIH, 39 with CHB, 14 with NAFLD and 45 healthy controls, and thereafter a liver targeted determination in 27 PBC, 27 AIH, 20 CHB, 14 NAFLD and 6 controls. We thence focused on mechanisms of this expansion using PBC as an example using both UDCA naive and treated patients. HLA-DR^-/lowCD33⁺CD11b⁺CD14⁺CD15^- monocytic MDSCs were elevated in diseases characterized by liver inflammation compared to healthy controls. Using PBC as a focus there was a significant correlation between levels of circulating MDSCs and disease related biochemical markers (ALP, TBIL). Second, there were higher amounts of MDSCs in PBC patients that were responsive to UDCA. Third, MDSCs from PBC manifest potent immunosuppressive function. There was a significant correlation in the accumulation of hepatic MDSCs in the inflamed lesions of PBC with histological changes such as fibrosis. Lastly, CCN1, a highly expressed protein in impaired cholangiocytes and hepatocytes, contribute to MDSCs expansion and MDSC-inducible nitric oxide synthase (iNOS) associated immune suppression. In conclusion, CCN1 modulate expansion and suppressive function of MDSCs. Our data highlight the potential functions of CCN1 on MDSCs and suggest therapeutic implications in inflammatory liver diseases. This article is protected by copyright. All rights reserved.

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