Autophagy mediates the process of cellular senescence characterizing bile duct damages in primary biliary cirrhosis

Abstract

Recent studies disclosed that autophagy is induced during and facilitates the process of senescence. Given that biliary epithelial cells (BECs) in damaged small bile ducts in primary biliary cirrhosis (PBC) show senescent features, we examined an involvement of autophagy in the process of biliary epithelial senescence in PBC. We examined immunohistochemically the expression of microtubule-associated proteins-light chain 3b (LC3), a marker of autophagy, in livers taken from the patients with PBC (n ¼ 37) and control livers (n ¼ 75). We also examined the co-localization of LC3 with autophagy-related cathepsin D, lysosome-associated membrane protein-1 (LAMP-1), and senescent markers, p16INK4a and p21 WAF1/Cip1 . We examined the effect of autophagy inhibitor (3-methyladenine) on the induction of cellular senescence and senescence-associated secretion (CCL2 and CX3CL1) in cultured murine BECs. The expression of LC3 was specifically seen in vesicles in BECs in the inflamed and damaged small bile ducts in PBC, when compared with non-inflamed small bile ducts in PBC and in control livers (Po0.01). The expression of LC3 was closely related to the expression of cathepsin D, LAMP-1, and senescent markers. In cultured BECs, oxidative stress, DNA damage, and serum deprivation induced cellular senescence, when compared with control and the inhibition of autophagy significantly decreased the stress-induced cellular senescence (Po0.01). Furthermore, the secretion level of CCL2 and CX3CL1 increased significantly by various stress and suppressed by the inhibition of autophagy (Po0.01). In conclusion, autophagy is specifically seen in the damaged small bile ducts along with cellular senescence in PBC. The inhibition of autophagy suppressed cellular senescence in cultured cells. These findings suggest that autophagy may mediate the process of biliary epithelial senescence and involve in the pathogenesis of bile duct lesions in PBC. Autophagy and cellular senescence are two distinct cellular responses to stress. An appropriate cellular stress response is critical for maintaining tissue integrity and function and for preventing diseases. Cells respond to stress with adaptation, repair, and recovery, or are diverted into irreversible cell-cycle exit (senescence) or are eliminated through programmed cell death (apoptosis). 1 Autophagy is a genetically regulated program responsible for the turnover of cellular proteins and damaged organelles. This evolutionarily conserved process is characterized by the formation of double membrane cytosolic vesicles, autophagosomes, which sequester cytoplasmic content and deliver it to lysosomes. 2,3 Autophagy is often associated with acute metabolic changes and rapid protein replacement. Microtubule-associated proteins-light chain 3b (LC3), a homolog of autophagy-related protein 8, which is essential for autophagy and associated to the autophagosome membranes after processing, is a widely used marker of autophagy. 4,5 Autophagy can enable adaptation to stress through the degradation of cellular protei...

Autophagy May Precede Cellular Senescence of Bile Ductular Cells in Ductular Reaction in Primary Biliary Cirrhosis

“…This finding clearly indicates that autophagy is involved in the pathogenesis of DR in PBC and DR in PBC may be different from other liver disease. We have shown that autophagy is upregulated in the damage bile ducts in PBC (20). Therefore, the autophagy appears to be a common feature of biliary epithelial cells in small bile ducts and DR in PBC.…”

“…senescence (22) and we have also reported that autophagy mediates biliary epithelial senescence (20). Our previous study shows that some of ductular cells in DR in chronic liver diseases were at G1-arrest and undergoing cellular senescence and that such senescent cells may be involved in the progression of fibrosis of these diseases, particularly in PBC (6).…”

“…We have also reported that autophagy may precedes biliary epithelial senescence in the damaged bile ducts in primary biliary cirrhosis (PBC) (20). Although cellular senescence is involved in the pathophysiology of DR along with fibrous progression in primary biliary cirrhosis (PBC) (4-6), there has been no study reporting the involvement of autophagy in ductular cells in PD.…”

Autophagy Induces Prosenescent Changes in Proximal Tubular S3 Segments

“…[9][10][11][12] In summary, the observation that autophagy facilitates the establishment of a senescence phenotype and prevents clearance of potentially harmful cells is crucial in light of potential novel therapies to treat AKI by unselective enhancement of autophagy. 7 Additional research should focus on strategies for modulating autophagy that can be adapted for varied conditions and individual cellular stress levels.…”

“…8 Importantly, activation of both processes might be functionally linked: autophagy can facilitate senescence induction under various circumstances and in various cell types. [9][10][11] The underlying molecular mechanism explaining this prosenescent nature might be the need of autophagic degradation of an inhibitory isoform of p53 to suppress replicative senescence. 12 To test the potential interdependence of autophagy and cellular senescence, autophagy-related 5 (Atg5) protein was deleted in tubular epithelial cells.…”