Autophagy and senescence in fibrosing cholangiopathies Yasuni Nakanuma, Motoko Sasaki, Kenichi Harada  Journal of Hepatology  Volume 62, Issue 4, Pages 934-945 (April 2015) DOI: 10.1016/j.jhep.2014.11.027 Copyright © 2014 European Association for the Study of the Liver Terms and Conditions

Fig. 1 Cellular responses to stress. Apoptosis, autophagy, and cellular senescence are distinct cellular responses to stress. Autophagy is induced in response to a wide variety of stresses, and there are many purposes for autophagy such as the quality control of protein and organelle, damage mitigation, and energy homeostasis. Stressed cells activate autophagy, which prevents damage and maintains metabolism though lysosomal turnover of cellular components. Autophagy can facilitate senescence or limit damage and delay apoptosis to allow recovery and repair of normal cell function (modified from [12]). Journal of Hepatology 2015 62, 934-945DOI: (10.1016/j.jhep.2014.11.027) Copyright © 2014 European Association for the Study of the Liver Terms and Conditions

Fig. 2 Innate immunity and physiopathological reactions in cholangiocytes. Activated innate immunity of cholangiocytes upon ligation of surface Toll-like receptors (TLRs) by pathogen-associated molecular patterns (PAMPs), induce several effector pathways. Representative effector: i) Persistent peribiliary fibroinflammation by secretion of chemokines and cytokines, ii) defense against bacterial and viral infection by IFN-β and antimicrobial peptides (defensin), iii) cellular senescence by activation of N-Ras (oncogene-induced senescence), iv) cell proliferation associated with IL-6, v) cell survive with features of “non-epithelial” cells and fibrosis, and vi) apoptosis induced by tumor factor-related apoptosis-inducing ligand (TRAIL) (EMT, epithelial-mesenchymal transition). Journal of Hepatology 2015 62, 934-945DOI: (10.1016/j.jhep.2014.11.027) Copyright © 2014 European Association for the Study of the Liver Terms and Conditions

Fig. 3 A hypothesis on the association of deregulated autophagy of cholangiocytes as autoimmune reaction of primary biliary cirrhosis. Autophagy is implicated in the intracellular antigen processing required for the presentation of major histocompatibility complex (MHC) class I and class II. Recycling of autolysosomes is deregulated, and this may be implicated in increased autophagosomes with increased expression of p62 and LC3 as well as disordered intracellular antigen processing with the presentation of MHC class I and class II. The cell-surface expression of mitochondrial antigen such as PDC-E2 and of MHC class I or class II molecules on cholangiocytes could lead to antigen presentation by MHC class I and II to immunocompetent cells such as dendritic cells, as well as to a direct target antigen recognition by PDC-E2-specific cytotoxic T cells, followed by autoimmune reactions. Journal of Hepatology 2015 62, 934-945DOI: (10.1016/j.jhep.2014.11.027) Copyright © 2014 European Association for the Study of the Liver Terms and Conditions

Fig. 4 Possible pathogenesis of fibrosing cholangiopathy of primary sclerosing cholangitis with respect to cellular senescence and deregulated innate immunity. Cell injuries including enteric microbes or their products (PAMPs) and autoantibody against biliary epithelial cells (BEC-Ab) may be involved in the cellular senescence and senescence-associated secretory phenotype (SASP) and deregulated innate immunity. Senescent cholangiocytes and activated cholangiocytes by innate immunity may participate in modulation of the inflammatory microenvironment by secreting chemocytes, cytokines, growth factors, protease MMPs, and PAI-1 (SASP) followed by recruiting monocytes and possibly other types of inflammatory cells, induction of senescence in surrounding connective tissue cells (bystander effects) and progression of epithelial-mesenchymal transition (EMT) and fibrosis (PAMPs, pathogen-associated molecular patterns). Journal of Hepatology 2015 62, 934-945DOI: (10.1016/j.jhep.2014.11.027) Copyright © 2014 European Association for the Study of the Liver Terms and Conditions

Journal of Hepatology 2015 62, 934-945DOI: (10. 1016/j. jhep. 2014. 11 Copyright © 2014 European Association for the Study of the Liver Terms and Conditions