Elevated circulating CD14^lowCD16⁺ monocyte subset in primary biliary cirrhosis correlates with liver injury and promotes Th1 polarization

Abstract

Primary biliary cirrhosis (PBC) is a progressive autoimmune liver disease in which monocytes/macrophages infiltration and skewed T helper type (Th) 1 and Th17 cell responses participate in the development of the disease. Human peripheral blood monocytes are heterogeneous and can be divided into classical CD14^highCD16⁻, intermediate CD14^highCD16⁺, and nonclassical CD14^lowCD16⁺ monocyte subsets. Compared to classical monocytes, CD16⁺ monocytes are generally termed pro-inflammatory monocytes and play an important pathogenic role in autoimmune diseases. However, little is known about the immunophenotype and immunopathogenic role of peripheral blood CD16⁺ monocytes in PBC. Thus, we investigated the phenotype and function of these circulating monocyte subsets from PBC patients. The frequencies of circulating CD14^highCD16⁺ and CD14^lowCD16⁺ subpopulation were increased in disease compared with healthy controls. Among them, CD14^lowCD16⁺ monocyte subset positively correlated with disease progress, liver damage indicators and serum C-reactive protein, respectively. Furthermore, the frequencies of Th1 and Th17 cells were upregulated and CD14^lowCD16⁺ monocyte subset was also positively associated with Th1 cell frequency in PBC. Using a vitro coculture model, we further found that CD14^lowCD16⁺ monocytes promoted Th1 cell polarization compared to classical monocytes. Interleukin-12 (IL-12) and direct contact of patient CD4⁺T cell and CD14^lowCD16⁺ monocytes, were responsible for CD14^lowCD16⁺ monocytes promotion of Th1 cells polarization in PBC. Our study demonstrated that the enhanced CD14^lowCD16⁺ monocyte subset participated in fostering liver damage and inflammatory responses, and promoted Th1 cells skewing in PBC.