Autophagy and senescence in fibrosing cholangiopathies

Abstract

Fibrosing cholangiopathy such as primary sclerosing cholangitis (PSC) and biliary atresia (BA) is characterized by biliary epithelial injuries and concentric fibrous obliteration of the biliary tree together with inflammatory cell infiltration. In these diseases, inappropriate innate immunity is reported to contribute more to bile duct pathology as compared with various aspects of "classical" autoimmune diseases. Primary biliary cirrhosis (PBC) is characterized by chronic cholangitis with bile duct loss and classical autoimmune features. Cellular senescence of cholangiocytes and a senescence-associated secretory phenotype lead to the production of proinflammatory cytokines and chemokines that may modify the milieu of the bile duct and then trigger fibroinflammatory responses in PSC and PBC. Furthermore, deregulated autophagy might be involved in cholangiocyte senescence and possibly in the autoimmune process in PBC, and the deregulated innate immunity against enteric microbes or their products that is associated with cholangiocyte senescence might result in the fibrosing cholangitis that develops in PBC and PSC. In BA, innate immunity against double-stranded RNA viruses might be involved in cholangiocyte apoptosis and also in the development of the epithelial-mesenchymal transition of cholangiocytes that results in fibrous obliteration of bile ducts. These recent advances in the understanding of immune-mediated biliary diseases represent a paradigm shift: the cholangiocyte is no longer viewed merely as a passive victim of injury; it is now also considered to function as a potential effector in bile duct pathology.

Primary Biliary Cholangitis: Its Pathological Characteristics and Immunopathological Mechanisms

“…Senescent biliary epithelial cells may modulate the microenvironment surrounding bile ducts by expressing senescence -associated secretory phenotypes (SASP) and contribute to maintaining inflammation and fibrosis around bile duct lesions in PBC. Deregulated autophagy followed by cellular senescence in biliary epithelial cells may be closely related to the abnormal expression of mitochondrial antigens and subsequent autoimmune pathogenesis in PBC (47,48). The biliary epithelial cells of PBC are exposed to excessive oxidative stress because of a decrease in their anti-oxidative abilities (49).…”

Bile Acids and Deregulated Cholangiocyte Autophagy in Primary Biliary Cholangitis

“…Cholangiocytes are injured by various stresses including hydrophobic bile acids such as glycochenodeoxycholic acid (GCDC) in cholangiopathies [1,2] . Impaired 'biliary HCO 3 -umbrella,' which is important to protect biliary physiology, may be a common pathological condition in primary biliary cholangitis (PBC) and other cholangiopathies [3,4] .…”

Is Cellular Senescence Involved in Progressive Loss of Canals of Hering in Primary Biliary Cirrhosis?

“…Although these cells are metabolically still active, this process is followed by eventual loss of affected cells. Recent studies showed that cellular senescence was implicated in several biliary diseases and also premature or stress-induced senescence was discussed with respect to senescence-associated secretory phenotype (SASP) which is associated with microenvironments of affected cells or tissues [11,12]. Interestingly, Sasaki et al reported that bile ductules showed cellular senescence in PBC, and that sustained cellular senescence might lead to the eventual loss of bile ductules and CoH loss [9,10].…”

“…Interestingly, Sasaki et al reported that bile ductules showed cellular senescence in PBC, and that sustained cellular senescence might lead to the eventual loss of bile ductules and CoH loss [9,10]. It is, moreover, reported that senescence is propagated through positive feedback by nearby senescent cells, causing senescence of adjacent bile ductules and CoH in PBC [11,12]. Recently, we have reported that cellular senescence may play an important role in the pathogenesis of fibrosing cholangiopathies including PBC, and senescence of biliary epithelial cells may be induced by several senescent stimuli, particularly impaired autophagy and oxidative stresses [11].…”

“…It is, moreover, reported that senescence is propagated through positive feedback by nearby senescent cells, causing senescence of adjacent bile ductules and CoH in PBC [11,12]. Recently, we have reported that cellular senescence may play an important role in the pathogenesis of fibrosing cholangiopathies including PBC, and senescence of biliary epithelial cells may be induced by several senescent stimuli, particularly impaired autophagy and oxidative stresses [11]. Alpini et al also reviewed cellular senescence and cholangiopathy, indicating that cellular senescence of cholangiocytes may be linked to the development of cholangiopathies of several biliary diseases, particularly PBC, primary sclerosing cholangitis, biliary atresia and chronic allograft rejection [12].…”