Intrahepatic macrophage populations in the pathophysiology of primary sclerosing cholangitis.
Background & Aims: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive inflammatory and fibrotic injury to the biliary tree. We sought to further delineate the contribution of macrophage lineages in PSC pathobiology. Methods: Human liver tissues and/or blood samples from patients with PSC, primary biliary cholangitis, other non-cholestatic/non-autoimmune diseases, including alcohol-related liver disease and non-alcoholic steatohepatitis, as well as normal liver, were sourced from our liver transplantation program. Liver fibrosis was studied using Van Gieson staining, while the frequencies of infiltrating monocyte and macrophage lineages, both in the circulation and the liver, were investigated by flow cytometry, including the expression of TGR-5, a G protein-coupled receptor (GPBAR1/TGR-5). Results: Significantly higher frequencies of CD68+CD206+ macrophages were detected in the livers of patients with PSC (median 19.17%; IQR 7.25-32.8%; n = 15) compared to those of patients with other liver diseases (median 12.05%; IQR 5.61-16.03%; n = 12; p = 0.0373). CD16+ monocytes, including both intermediate (CD14+CD16++) and non-classical (CD14dimCD16++) monocytes, were preferentially recruited into chronically diseased livers, with the highest recruitment ratios in PSC (median 15.83%; IQR 9.66-29.5%; n = 15), compared to other liver diseases (median 6.66%; IQR 2.88-11.64%, n = 14, p = 0.0152). The expression of TGR-5 on CD68+ intrahepatic macrophages was increased in chronic liver disease; TGR-5 expression on intrahepatic macrophages was highest in PSC (median 36.32%; IQR 17.71-63.61%; n = 6) and most TGR-5+ macrophages were CD68+CD206+ macrophages. Conclusions: Underlying a potential role for macrophages in PSC pathobiology, we demonstrate, using patient-derived tissue, increased CD16+ monocyte recruitment and a higher frequency of CD68+CD206+ macrophages in the livers of patients with PSC; the CD68+CD206+ macrophage subset was associated with significantly higher TGR-5 expression in PSC.
|Authors:||Chen YY, Arndtz K, Webb G, Corrigan M, Akiror S, Liaskou E, Woodward P, Adams DH, Weston CJ, Hirschfield GM.|
|Journal:||JHEP Rep. 2019 Oct 31;1(5):369-376|
|PubMed:||Find in PubMed|