The Emerging Role of Macrophages in Chronic Cholangiopathies Featuring Biliary Fibrosis: An Attractive Therapeutic Target for Orphan Diseases

Abstract

Cholangiopathies are a heterogeneous group of chronic liver diseases caused by different types of injury targeting the biliary epithelium, such as genetic defects and immune-mediated attacks. Notably, most cholangiopathies are orphan, thereby representing one of the major gaps in knowledge of the modern hepatology. A typical hallmark of disease progression in cholangiopathies is portal scarring, and thus development of effective therapeutic approaches would aim to hinder cellular and molecular mechanisms underpinning biliary fibrogenesis. Recent lines of evidence indicate that macrophages, rather than more conventional cell effectors of liver fibrosis such as hepatic stellate cells and portal fibroblasts, are actively involved in the earliest stages of biliary fibrogenesis by exchanging a multitude of cues with cholangiocytes, which promote their recruitment from the circulating compartment owing to a senescent or an immature epithelial phenotype. Two cholangiopathies, namely primary sclerosing cholangitis and congenital hepatic fibrosis, are paradigmatic of this mechanism. This review summarizes current understandings of the cytokine and extracellular vesicles-mediated communications between cholangiocytes and macrophages typically occurring in the two cholangiopathies to unveil potential novel targets for the treatment of biliary fibrosis.

Molecular characterization and cell type composition deconvolution of fibrosis in NAFLD

“…Between the two published gene signatures there is one overlapping gene, TNFRSF12A . Interestingly, IL32 has been previously reported as the top up-regulated liver transcript in NAFLD 39 . We also checked the 25-gene signature from 10 in our cluster analysis, with 17 of the 25 genes corresponding to cluster 2 ( CCL20 , CFAP221 , DTNA , DUSP8 , IL32 , ITGBL1 , STMN2 , TNFRSF12A ), cluster #3 ( COL1A1 , COL1A2 , LTBP2 , PDGFA , RGS4 , THY1 ) and cluster 5 ( AKR1B10 , CLIC6 , TYMS ) of up-regulated genes.…”

“…6 underscores previously described molecular influences on the fibrotic microenvironment 12 . Molecular cues from damaged hepatocytes activate aberrant intercellular cross-talk between heterogenous monocyte-derived macrophage subpopulations 39 and hepatic cells to orchestrate a progressive fibrotic niche 12 , 19 , 23 . Our data identified potential key drivers of these pathways within the deconvoluted macrophage, cholangiocyte, HSC, and hepatocyte specific genes in the signature.…”

Dysregulation of the Scribble/YAP/β‐catenin axis sustains the fibroinflammatory response in a PKHD1 −/− mouse model of congenital hepatic fibrosis

“…Inhibition of β‐catenin signaling is responsible for a lower local concentration of β‐catenin‐dependent profibrotic chemokines around the biliary structures resulting in a reduction of the pericystic inflammatory infiltrate. In turn, the reduced number of inflammatory cells account for a diminished secretion of cytokines trophic for the biliary epithelium, with a consequent reduction in the size of the cysts paralleled by a reduced deposition of fibrosis 49,50 …”

Mitigation of portal fibrosis and cholestatic liver disease in ANKS6 ‐deficient livers by macrophage depletion

“…CHF is a heterogeneous cholangiopathy that frequently manifests as part of cilia‐related syndromic disorders, such as autosomal recessive polycystic kidney disease (OMIM #263200), Meckel‐Gruber syndrome (OMIM #249000), Joubert syndrome (OMIM #213300), Bardet‐Biedl syndrome (OMIM #209900), nephronophthisis (NPHP) (OMIM #256100), or oral‐facial‐digital syndrome (OMIM #311200), indicating that ciliary dysfunction which underpins the ductal plate remodeling abnormalities in these disorders can secondarily lead to progressive fibrogenesis in the portal tract 10,33,34 . Indeed, work by several groups, including ours, have demonstrated that defective bile duct morphogenesis gives rise to damaged and immature cholangiocytes, which secrete different profibrotic cytokines (Tgfb1) and growth factors (Ctgf) that promote cell proliferation and fibrogenesis in the surrounding tissue 7,35,36 .…”