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Cited by 38Liver Diseases and ImmunityLiver physiology and pathologyPediatric Hepatobiliary Diseases and Treatments

Central role for cholangiocyte pathobiology in cholestatic liver diseases

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Jalan-Sakrikar, Nidhi, Guicciardi, Maria Eugenia, O’Hara, Steven P., Azad, Adiba, LaRusso, Nicholas F., Gores, Gregory J., Huebert, Robert C.·2025·Hepatology
DOI 10.1097/hep.0000000000001093PMC PMC11890218
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Abstract

Cholangiopathies comprise a spectrum of chronic intrahepatic and extrahepatic biliary tract disorders culminating in progressive cholestatic liver injury, fibrosis, and often cirrhosis and its sequela. Treatment for these diseases is limited, and collectively, they are one of the therapeutic “black boxes” in clinical hepatology. The etiopathogenesis of the cholangiopathies likely includes disease-specific mediators but also common cellular and molecular events driving disease progression (eg, cholestatic fibrogenesis, inflammation, and duct damage). The common pathways involve cholangiocytes, the epithelial cells lining the intrahepatic and extrahepatic bile ducts, which are central to the pathogenesis of these disorders. Current information suggests that cholangiocytes function as a signaling “hub” in biliary tract-associated injury. Herein, we review the pivotal role of cholangiocytes in cholestatic fibrogenesis, focusing on the crosstalk between cholangiocytes and portal fibroblasts and HSCs. The proclivity of these cells to undergo a senescence-associated secretory phenotype, which is proinflammatory and profibrogenic, and the intrinsic intracellular activation pathways resulting in the secretion of cytokines and chemokines are reviewed. The crosstalk between cholangiocytes and cells of the innate (neutrophils and macrophages) and adaptive (T cells and B cells) immune systems is also examined in detail. The information will help consolidate information on this topic and guide further research and potential therapeutic strategies for these diseases.

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  • Biliary epithelial cells (BECs) and their derivatives, often referred to as ductular cells in liver diseases, play a key role in many liver diseases, as the transport of bile to the intestine is a central liver function that needs to be preserved to avoid toxic effects on the liver.

    “Biliary epithelial cells (BECs) and their derivatives, often referred to as ductular cells in liver diseases, play a key role in many liver diseases, as the transport of bile to the intestine is a central liver function that needs to be preserved to avoid toxic effects on the liver.”

    From Inflammation and immunity in liver homeostasis and disease: a nexus of hepatocytes, nonparenchymal cells and immune cells (2025) · cites this paper as [157]

  • The microanatomic niche of BECs predisposes them to interact with many other cell types, including immune cells, and renders the periductular area a common site of inflammation.

    “Moreover, their microanatomic niche predisposes BECs to interact with many other cell types, including immune cells, and renders the periductular area a common site of inflammation [155–157].”

    From Inflammation and immunity in liver homeostasis and disease: a nexus of hepatocytes, nonparenchymal cells and immune cells (2025) · cites this paper as [157]

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References 184 · Cited by 38

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  1. Banales JM, Huebert RC, Karlsen T, Strazzabosco M, LaRusso NF, Gores GJ. Cholangiocyte pathobiology. Nat Rev Gastroenterol Hepatol 2019;16:269-281. [PubMed: 30850822]
  2. Alpini G, Glaser SS, Ueno Y, Rodgers R, Phinizy JL, Francis H, Baiocchi L, et al. Bile acid feeding induces cholangiocyte proliferation and secretion: evidence for bile acid-regulated ductal secretion. Gastroenterology 1999;116:179-186. [PubMed: 9869616]
  3. Alvaro D, Gigliozzi A, Attili AF. Regulation and deregulation of cholangiocyte proliferation. J Hepatol 2000;33:333-340. [PubMed: 10952254]
  4. Demeulenaere L [Etiology & pathogenesis of cirrhogenic cholangiopathy]. Belg Tijdschr Geneesk 1957;13:651-655. [PubMed: 13436384]
  5. Demeulenaere L, Candaele N. [Cirrhogenic cholangiopathies after gastrointestinal interventions]. Arch Mal Appar Dig Mal Nutr 1957;46:1325-1329. [PubMed: 13509833]
  6. Lazaridis KN, Strazzabosco M, Larusso NF. The cholangiopathies: disorders of biliary epithelia. Gastroenterology 2004;127:1565-1577. [PubMed: 15521023]
  7. Jiang X, Otterdal K, Chung BK, Maucourant C, Ronneberg JD, Zimmer CL, Ogaard J, et al. Cholangiocytes Modulate CD100 Expression in the Liver and Facilitate Pathogenic T-Helper 17 Cell Differentiation. Gastroenterology 2024;166:667-679. [PubMed: 37995866]
  8. Ceci L, Gaudio E, Kennedy L. Cellular Interactions and Crosstalk Facilitating Biliary Fibrosis in Cholestasis. Cell Mol Gastroenterol Hepatol 2024;17:553-565. [PubMed: 38216052]
  9. Arteel GE, Naba A. The liver matrisome -looking beyond collagens. JHEP Rep 2020;2:100115. [PubMed: 32637906]
  10. Cai X, Tacke F, Guillot A, Liu H. Cholangiokines: undervalued modulators in the hepatic microenvironment. Front Immunol 2023;14:1192840. [PubMed: 37261338]
  11. Aseem SO, Huebert RC. Epigenetic Mechanisms of Pancreatobiliary Fibrosis. Curr Treat Options Gastroenterol 2019;17:342-356. [PubMed: 31300946]
  12. Aseem SO, Jalan-Sakrikar N, Chi C, Navarro-Corcuera A, De Assuncao TM, Hamdan FH, Chowdhury S, et al. Epigenomic Evaluation of Cholangiocyte Transforming Growth Factor-beta Signaling Identifies a Selective Role for Histone 3 Lysine 9 Acetylation in Biliary Fibrosis. Gastroenterology 2021;160:889-905 e810. [PubMed: 33058867]
  13. Ahuja S, Zaheer S. Multifaceted TGF-beta signaling, a master regulator: From bench-to-bedside, intricacies, and complexities. Cell Biol Int 2024;48:87-127. [PubMed: 37859532]
  14. Wang Z, Du K, Jin N, Tang B, Zhang W. Macrophage in liver Fibrosis: Identities and mechanisms. Int Immunopharmacol 2023;120:110357. [PubMed: 37224653]
  15. Siapoush S, Rezaei R, Alavifard H, Hatami B, Zali MR, Vosough M, Lorzadeh S, et al. Therapeutic implications of targeting autophagy and TGF-beta crosstalk for the treatment of liver fibrosis. Life Sci 2023;329:121894. [PubMed: 37380126]
  16. Deng Z, Fan T, Xiao C, Tian H, Zheng Y, Li C, He J. TGF-beta signaling in health, disease, and therapeutics. Signal Transduct Target Ther 2024;9:61. [PubMed: 38514615]
  17. De Assuncao TM, Sun Y, Jalan-Sakrikar N, Drinane MC, Huang BQ, Li Y, Davila JI, et al. Development and characterization of human-induced pluripotent stem cell-derived cholangiocytes. Lab Invest 2015;95:684-696. [PubMed: 25867762]
  18. Moretti L, Stalfort J, Barker TH, Abebayehu D. The interplay of fibroblasts, the extracellular matrix, and inflammation in scar formation. J Biol Chem 2022;298:101530. [PubMed: 34953859]
  19. Jalan-Sakrikar N, De Assuncao TM, Shi G, Aseem SO, Chi C, Shah VH, Huebert RC. Proteasomal Degradation of Enhancer of Zeste Homologue 2 in Cholangiocytes Promotes Biliary Fibrosis. Hepatology 2019;70:1674-1689. [PubMed: 31070797]
  20. Henderson NC, Rieder F, Wynn TA. Fibrosis: from mechanisms to medicines. Nature 2020;587:555-566. [PubMed: 33239795]
  21. Perugorria MJ, Olaizola P, Labiano I, Esparza-Baquer A, Marzioni M, Marin JJG, Bujanda L, et al. Wnt-beta-catenin signalling in liver development, health and disease. Nat Rev Gastroenterol Hepatol 2019;16:121-136. [PubMed: 30451972]
  22. Ayers M, Kosar K, Xue Y, Goel C, Carson M, Lee E, Liu S, et al. Inhibiting Wnt Signaling Reduces Cholestatic Injury by Disrupting the Inflammatory Axis. Cell Mol Gastroenterol Hepatol 2023;16:895-921. [PubMed: 37579970]
  23. Russell JO, Monga SP. Wnt/beta-Catenin Signaling in Liver Development, Homeostasis, and Pathobiology. Annu Rev Pathol 2018;13:351-378. [PubMed: 29125798]
  24. Kosar K, Cornuet P, Singh S, Lee E, Liu S, Gayden J, Sato T, et al. WNT7B Regulates Cholangiocyte Proliferation and Function During Murine Cholestasis. Hepatol Commun 2021;5:2019-2034. [PubMed: 34558852]
  25. Okabe H, Yang J, Sylakowski K, Yovchev M, Miyagawa Y, Nagarajan S, Chikina M, et al. Wnt signaling regulates hepatobiliary repair following cholestatic liver injury in mice. Hepatology 2016;64:1652-1666. [PubMed: 27533619]
  26. Pradhan-Sundd T, Zhou L, Vats R, Jiang A, Molina L, Singh S, Poddar M, et al. Dual catenin loss in murine liver causes tight junctional deregulation and progressive intrahepatic cholestasis. Hepatology 2018;67:2320-2337. [PubMed: 29023813]
  27. Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell 2002;110:673-687. [PubMed: 12297042]
  28. Wang J, Du M, Meng L, Yang Y, He S, Zhu Y, Ren X, et al. Integrative analysis implicates the significance of m6A in the liver fibrosis of biliary atresia by regulating THY1. Hepatol Commun 2023;7:e0004. [PubMed: 36633486]
  29. Patsenker E, Popov Y, Stickel F, Jonczyk A, Goodman SL, Schuppan D. Inhibition of integrin alphavbeta6 on cholangiocytes blocks transforming growth factor-beta activation and retards biliary fibrosis progression. Gastroenterology 2008;135:660-670. [PubMed: 18538673]
  30. Schaub JR, Chen JY, Turner SM. Integrins in biliary injury and fibrosis. Curr Opin Gastroenterol 2024;40:85-91. [PubMed: 38190346]
  31. Fiorucci S, Distrutti E. Bile Acid-Activated Receptors, Intestinal Microbiota, and the Treatment of Metabolic Disorders. Trends Mol Med 2015;21:702-714. [PubMed: 26481828]
  32. Cheung AC, Juran BD, Schlicht EM, McCauley BM, Atkinson EJ, Moore R, Heimbach JK, et al. DNA methylation profile of liver tissue in end-stage cholestatic liver disease. Epigenomics 2022;14:481-497. [PubMed: 35473391]
  33. Cofer ZC, Cui S, EauClaire SF, Kim C, Tobias JW, Hakonarson H, Loomes KM, et al. Methylation Microarray Studies Highlight PDGFA Expression as a Factor in Biliary Atresia. PLoS One 2016;11:e0151521. [PubMed: 27010479]
  34. McDaniel K, Meng F, Wu N, Sato K, Venter J, Bernuzzi F, Invernizzi P, et al. Forkhead box A2 regulates biliary heterogeneity and senescence during cholestatic liver injury in micedouble dagger. Hepatology 2017;65:544-559. [PubMed: 27639079]
  35. Rodrigues PM, Perugorria MJ, Santos-Laso A, Bujanda L, Beuers U, Banales JM. Primary biliary cholangitis: A tale of epigenetically-induced secretory failure? J Hepatol 2018;69:1371-1383. [PubMed: 30193962]
  36. Jalan-Sakrikar N, De Assuncao TM, Lu J, Almada LL, Lomberk G, Fernandez-Zapico ME, Urrutia R, et al. Hedgehog Signaling Overcomes an EZH2-Dependent Epigenetic Barrier to Promote Cholangiocyte Expansion. PLoS One 2016;11:e0168266. [PubMed: 27936185]
  37. O'Hara SP, Splinter PL, Trussoni CE, Pisarello MJ, Loarca L, Splinter NS, Schutte BF, et al. ETS Proto-oncogene 1 Transcriptionally Up-regulates the Cholangiocyte Senescence-associated Protein Cyclin-dependent Kinase Inhibitor 2A. J Biol Chem 2017;292:4833-4846. [PubMed: 28184004]
  38. O'Hara SP, Splinter PL, Trussoni CE, Guicciardi ME, Splinter NP, Al Suraih MS, Nasser-Ghodsi N, et al. The transcription factor ETS1 promotes apoptosis resistance of senescent cholangiocytes by epigenetically up-regulating the apoptosis suppressor BCL2L1. J Biol Chem 2019;294:18698- 18713. [PubMed: 31659122]
  39. Kang JH, Splinter PL, Trussoni CE, Pirius NE, Gores GJ, LaRusso NF, O'Hara SP. The Epigenetic Reader, Bromodomain Containing 2, Mediates Cholangiocyte Senescence via Interaction With ETS Proto-Oncogene 1. Gastroenterology 2023;165:228-243 e222. [PubMed: 37059338]
  40. Ji R, Chen J, Xie Y, Dou X, Qing B, Liu Z, Lu Y, et al. Multi-omics profiling of cholangiocytes reveals sex-specific chromatin state dynamics during hepatic cystogenesis in polycystic liver disease. J Hepatol 2023;78:754-769. [PubMed: 36681161]
  41. Kosters A, Karpen SJ. The role of inflammation in cholestasis: clinical and basic aspects. Semin Liver Dis 2010;30:186-194. [PubMed: 20422500]
  42. Trauner M, Fickert P, Stauber RE. Inflammation-induced cholestasis. J Gastroenterol Hepatol 1999;14:946-959. [PubMed: 10530489]
  43. Jansen PL, Ghallab A, Vartak N, Reif R, Schaap FG, Hampe J, Hengstler JG. The ascending pathophysiology of cholestatic liver disease. Hepatology 2017;65:722-738. [PubMed: 27981592]
  44. Cai SY, Boyer JL. The role of bile acids in cholestatic liver injury. Ann Transl Med 2021;9:737. [PubMed: 33987435]
  45. Duan S, Li X, Fan G, Liu R. Targeting bile acid signaling for the treatment of liver diseases: From bench to bed. Biomed Pharmacother 2022;152:113154. [PubMed: 35653887]
  46. Li T, Apte U. Bile Acid Metabolism and Signaling in Cholestasis, Inflammation, and Cancer. Adv Pharmacol 2015;74:263-302. [PubMed: 26233910]
  47. Guicciardi ME, Trussoni CE, LaRusso NF, Gores GJ. The Spectrum of Reactive Cholangiocytes in Primary Sclerosing Cholangitis. Hepatology 2020;71:741-748. [PubMed: 31833071]
  48. Liu T, Zhang L, Joo D, Sun SC. NF-kappaB signaling in inflammation. Signal Transduct Target Ther 2017;2:17023-. [PubMed: 29158945]
  49. Lawrence T The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol 2009;1:a001651. [PubMed: 20457564]
  50. Elssner C, Goeppert B, Longerich T, Scherr AL, Stindt J, Nanduri LK, Rupp C, et al. Nuclear Translocation of RELB Is Increased in Diseased Human Liver and Promotes Ductular Reaction and Biliary Fibrosis in Mice. Gastroenterology 2019;156:1190-1205 e1114. [PubMed: 30445013]
  51. Li Z, Li X, Su MB, Gao LX, Zhou YB, Yuan B, Lyu X, et al. Discovery of a Potent and Selective NF-kappaB-Inducing Kinase (NIK) Inhibitor That Has Anti-inflammatory Effects in Vitro and in Vivo. J Med Chem 2020;63:4388-4407. [PubMed: 32216342]
  52. Ren X, Li X, Jia L, Chen D, Hou H, Rui L, Zhao Y, et al. A small-molecule inhibitor of NF- kappaB-inducing kinase (NIK) protects liver from toxin-induced inflammation, oxidative stress, and injury. FASEB J 2017;31:711-718. [PubMed: 27871061]
  53. Schwabe RF, Seki E, Brenner DA. Toll-like receptor signaling in the liver. Gastroenterology 2006;130:1886-1900. [PubMed: 16697751]
  54. Zhang H, Leung PSC, Gershwin ME, Ma X. How the biliary tree maintains immune tolerance? Biochim Biophys Acta Mol Basis Dis 2018;1864:1367-1373. [PubMed: 28844953]
  55. O'Hara SP, Splinter PL, Trussoni CE, Gajdos GB, Lineswala PN, LaRusso NF. Cholangiocyte N-Ras protein mediates lipopolysaccharide-induced interleukin 6 secretion and proliferation. J Biol Chem 2011;286:30352-30360. [PubMed: 21757746]
  56. Chen XM, O'Hara SP, Nelson JB, Splinter PL, Small AJ, Tietz PS, Limper AH, et al. Multiple TLRs are expressed in human cholangiocytes and mediate host epithelial defense responses to Cryptosporidium parvum via activation of NF-kappaB. J Immunol 2005;175:7447-7456. [PubMed: 16301652]
  57. Fiorotto R, Scirpo R, Trauner M, Fabris L, Hoque R, Spirli C, Strazzabosco M. Loss of CFTR affects biliary epithelium innate immunity and causes TLR4-NF-kappaB-mediated inflammatory response in mice. Gastroenterology 2011;141:1498-1508, 1508 e1491-1495. [PubMed: 21712022]
  58. Mueller T, Beutler C, Pico AH, Shibolet O, Pratt DS, Pascher A, Neuhaus P, et al. Enhanced innate immune responsiveness and intolerance to intestinal endotoxins in human biliary epithelial cells contributes to chronic cholangitis. Liver Int 2011;31:1574-1588. [PubMed: 22093333]
  59. Spirli C, Fabris L, Duner E, Fiorotto R, Ballardini G, Roskams T, Larusso NF, et al. Cytokine- stimulated nitric oxide production inhibits adenylyl cyclase and cAMP-dependent secretion in cholangiocytes. Gastroenterology 2003;124:737-753. [PubMed: 12612912]
  60. Zhang R, Nakao T, Luo J, Xue Y, Cornuet P, Oertel M, Kosar K, et al. Activation of WNT/ Beta-Catenin Signaling and Regulation of the Farnesoid X Receptor/Beta-Catenin Complex After Murine Bile Duct Ligation. Hepatol Commun 2019;3:1642-1655. [PubMed: 31832572]
  61. Munshi MK, Priester S, Gaudio E, Yang F, Alpini G, Mancinelli R, Wise C, et al. Regulation of biliary proliferation by neuroendocrine factors: implications for the pathogenesis of cholestatic liver diseases. Am J Pathol 2011;178:472-484. [PubMed: 21281779]
  62. Bertolini A, Fiorotto R, Strazzabosco M. Bile acids and their receptors: modulators and therapeutic targets in liver inflammation. Semin Immunopathol 2022;44:547-564. [PubMed: 35415765]
  63. Xia X, Francis H, Glaser S, Alpini G, LeSage G. Bile acid interactions with cholangiocytes. World J Gastroenterol 2006;12:3553-3563. [PubMed: 16773712]
  64. Lenci I, Milana M, Signorello A, Grassi G, Baiocchi L. Secondary bile acids and the biliary epithelia: The good and the bad. World J Gastroenterol 2023;29:357-366. [PubMed: 36687129]
  65. Lazaridis KN, Pham L, Tietz P, Marinelli RA, deGroen PC, Levine S, Dawson PA, et al. Rat cholangiocytes absorb bile acids at their apical domain via the ileal sodium-dependent bile acid transporter. J Clin Invest 1997;100:2714-2721. [PubMed: 9389734]
  66. Wang Y, Aoki H, Yang J, Peng K, Liu R, Li X, Qiang X, et al. The role of sphingosine 1-phosphate receptor 2 in bile-acid-induced cholangiocyte proliferation and cholestasis-induced liver injury in mice. Hepatology 2017;65:2005-2018. [PubMed: 28120434]
  67. Keitel V, Haussinger D. TGR5 in the biliary tree. Dig Dis 2011;29:45-47. [PubMed: 21691103]
  68. Reich M, Deutschmann K, Sommerfeld A, Klindt C, Kluge S, Kubitz R, Ullmer C, et al. TGR5 is essential for bile acid-dependent cholangiocyte proliferation in vivo and in vitro. Gut 2016;65:487-501. [PubMed: 26420419]
  69. Baghdasaryan A, Claudel T, Gumhold J, Silbert D, Adorini L, Roda A, Vecchiotti S, et al. Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2-/-(Abcb4-/-) mouse cholangiopathy model by promoting biliary HCO(-)(3) output. Hepatology 2011;54:1303- 1312. [PubMed: 22006858]
  70. Kirkland JL, Tchkonia T. Cellular Senescence: A Translational Perspective. EBioMedicine 2017;21:21-28. [PubMed: 28416161]
  71. St Sauver JL, Boyd CM, Grossardt BR, Bobo WV, Finney Rutten LJ, Roger VL, Ebbert JO, et al. Risk of developing multimorbidity across all ages in an historical cohort study: differences by sex and ethnicity. BMJ Open 2015;5:e006413.
  72. Tabibian JH, O'Hara SP, Splinter PL, Trussoni CE, LaRusso NF. Cholangiocyte senescence by way of N-ras activation is a characteristic of primary sclerosing cholangitis. Hepatology 2014;59:2263- 2275. [PubMed: 24390753]
  73. Cazzagon N, Sarcognato S, Floreani A, Corra G, De Martin S, Guzzardo V, Russo FP, et al. Cholangiocyte senescence in primary sclerosing cholangitis is associated with disease severity and prognosis. JHEP Rep 2021;3:100286. [PubMed: 34041468]
  74. Sasaki M, Kuo FY, Huang CC, Swanson PE, Chen CL, Chuang JH, Yeh MM. Increased expression of senescence-associated cell cycle regulators in the progression of biliary atresia: an immunohistochemical study. Histopathology 2018;72:1164-1171. [PubMed: 29392752]
  75. Jannone G, Bonaccorsi Riani E, de Magnee C, Tambucci R, Evraerts J, Ravau J, Baldin P, et al. Senescence and senotherapies in biliary atresia and biliary cirrhosis. Aging (Albany NY) 2023;15:4576-4599. [PubMed: 37204430]
  76. Sasaki M, Miyakoshi M, Sato Y, Nakanuma Y. Modulation of the microenvironment by senescent biliary epithelial cells may be involved in the pathogenesis of primary biliary cirrhosis. J Hepatol 2010;53:318-325. [PubMed: 20570384]
  77. Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res 1961;25:585-621. [PubMed: 13905658]
  78. Fumagalli M, Rossiello F, Clerici M, Barozzi S, Cittaro D, Kaplunov JM, Bucci G, et al. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat Cell Biol 2012;14:355-365. [PubMed: 22426077]
  79. McHugh D, Gil J. Senescence and aging: Causes, consequences, and therapeutic avenues. J Cell Biol 2018;217:65-77. [PubMed: 29114066]
  80. Sasaki M, Ikeda H, Haga H, Manabe T, Nakanuma Y. Frequent cellular senescence in small bile ducts in primary biliary cirrhosis: a possible role in bile duct loss. J Pathol 2005;205:451-459. [PubMed: 15685690]
  81. Sasaki M, Sato Y, Nakanuma Y. Increased p16(INK4a)-expressing senescent bile ductular cells are associated with inadequate response to ursodeoxycholic acid in primary biliary cholangitis. J Autoimmun 2020;107:102377. [PubMed: 31812332]
  82. Sanada Y, Aida J, Kawano Y, Nakamura K, Shimomura N, Ishikawa N, Arai T, et al. Hepatocellular telomere length in biliary atresia measured by Q-FISH. World J Surg 2012;36:908- 916. [PubMed: 22311140]
  83. Prata L, Ovsyannikova IG, Tchkonia T, Kirkland JL. Senescent cell clearance by the immune system: Emerging therapeutic opportunities. Semin Immunol 2018;40:101275. [PubMed: 31088710] 100.
  84. Huda N, Liu G, Hong H, Yan S, Khambu B, Yin XM. Hepatic senescence, the good and the bad. World J Gastroenterol 2019;25:5069-5081. [PubMed: 31558857] 101. Campisi J, d'Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 2007;8:729-740. [PubMed: 17667954] 102. Trussoni CE, O'Hara SP, LaRusso NF. Cellular senescence in the cholangiopathies: a driver of immunopathology and a novel therapeutic target. Semin Immunopathol 2022;44:527-544. [PubMed: 35178659] 103. Ferreira-Gonzalez S, Lu WY, Raven A, Dwyer B, Man TY, O'Duibhir E, Lewis PJS, et al. Paracrine cellular senescence exacerbates biliary injury and impairs regeneration. Nat Commun 2018;9:1020. [PubMed: 29523787] 104.
  85. Moncsek A, Al-Suraih MS, Trussoni CE, O'Hara SP, Splinter PL, Zuber C, Patsenker E, et al. Targeting senescent cholangiocytes and activated fibroblasts with B-cell lymphoma-extra large inhibitors ameliorates fibrosis in multidrug resistance 2 gene knockout (Mdr2(-/-)) mice. Hepatology 2018;67:247-259. [PubMed: 28802066] 106.
  86. Alsuraih M, O'Hara SP, Woodrum JE, Pirius NE, LaRusso NF. Genetic or pharmacological reduction of cholangiocyte senescence improves inflammation and fibrosis in the Mdr2 (-/-) mouse. JHEP Rep 2021;3:100250. [PubMed: 33870156] 107.
  87. Maroni L, Pinto C, Giordano DM, Saccomanno S, Banales JM, Spallacci D, Albertini MC, et al. Aging-Related Expression of Twinfilin-1 Regulates Cholangiocyte Biological Response to Injury. Hepatology 2019;70:883-898. [PubMed: 30561764] 108.
  88. Kyritsi K, Francis H, Zhou T, Ceci L, Wu N, Yang Z, Meng F, et al. Downregulation of p16 Decreases Biliary Damage and Liver Fibrosis in the Mdr2(/) Mouse Model of Primary Sclerosing Cholangitis. Gene Expr 2020;20:89-103. [PubMed: 32393417] 109. Jalan-Sakrikar N, De Assuncao TM, Navarro-Corcuera A, Hamdan FH, Loarca L, Kirkeby LA, Resch ZT, et al. Induced Pluripotent Stem Cells From Subjects With Primary Sclerosing Cholangitis Develop a Senescence Phenotype Following Biliary Differentiation. Hepatol Commun 2022;6:345-360. [PubMed: 34519176] 110.
  89. Guicciardi ME, Trussoni CE, Krishnan A, Bronk SF, Lorenzo Pisarello MJ, O'Hara SP, Splinter PL, et al. Macrophages contribute to the pathogenesis of sclerosing cholangitis in mice. J Hepatol 2018;69:676-686. [PubMed: 29802947] 111. Chen YY, Arndtz K, Webb G, Corrigan M, Akiror S, Liaskou E, Woodward P, et al. Intrahepatic macrophage populations in the pathophysiology of primary sclerosing cholangitis. JHEP Rep 2019;1:369-376. [PubMed: 32039388] 112.
  90. Arino S, Aguilar-Bravo B, Coll M, Lee WY, Peiseler M, Cantallops-Vila P, Sererols-Vinas L, et al. Ductular reaction-associated neutrophils promote biliary epithelium proliferation in chronic liver disease. J Hepatol 2023;79:1025-1036. [PubMed: 37348790] 114.
  91. Ronca V, Mancuso C, Milani C, Carbone M, Oo YH, Invernizzi P. Immune system and cholangiocytes: A puzzling affair in primary biliary cholangitis. J Leukoc Biol 2020;108:659- 671. [PubMed: 32349179] 115.
  92. Strazzabosco M, Fiorotto R, Cadamuro M, Spirli C, Mariotti V, Kaffe E, Scirpo R, et al. Pathophysiologic implications of innate immunity and autoinflammation in the biliary epithelium. Biochim Biophys Acta Mol Basis Dis 2018;1864:1374-1379. [PubMed: 28754453] 116.
  93. Nakanuma Y, Sasaki M, Harada K. Autophagy and senescence in fibrosing cholangiopathies. J Hepatol 2015;62:934-945. [PubMed: 25435435] 117.
  94. De Muynck K, Vanderborght B, De Ponti FF, Gijbels E, Van Welden S, Guilliams M, Scott CL, et al. Kupffer Cells Contested as Early Drivers in the Pathogenesis of Primary Sclerosing Cholangitis. Am J Pathol 2023;193:366-379. [PubMed: 36642171] 118.
  95. Duffield JS, Forbes SJ, Constandinou CM, Clay S, Partolina M, Vuthoori S, Wu S, et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest 2005;115:56-65. [PubMed: 15630444] 120.
  96. Stankey CT, Bourges C, Haag LM, Turner-Stokes T, Piedade AP, Palmer-Jones C, Papa I, et al. A disease-associated gene desert directs macrophage inflammation through ETS2. Nature 2024;630:447-456. [PubMed: 38839969] 123.
  97. Cho Y, Szabo G. Two Faces of Neutrophils in Liver Disease Development and Progression. Hepatology 2021;74:503-512. [PubMed: 33314193] 124.
  98. Aguilar-Bravo B, Rodrigo-Torres D, Arino S, Coll M, Pose E, Blaya D, Graupera I, et al. Ductular Reaction Cells Display an Inflammatory Profile and Recruit Neutrophils in Alcoholic Hepatitis. Hepatology 2019;69:2180-2195. [PubMed: 30565271] 125.
  99. Gujral JS, Farhood A, Bajt ML, Jaeschke H. Neutrophils aggravate acute liver injury during obstructive cholestasis in bile duct-ligated mice. Hepatology 2003;38:355-363. [PubMed: 12883479] 126.
  100. Gujral JS, Liu J, Farhood A, Hinson JA, Jaeschke H. Functional importance of ICAM-1 in the mechanism of neutrophil-induced liver injury in bile duct-ligated mice. Am J Physiol Gastrointest Liver Physiol 2004;286:G499-507. [PubMed: 14563671] 127.
  101. Takeuchi M, Vidigal PT, Guerra MT, Hundt MA, Robert ME, Olave-Martinez M, Aoki S, et al. Neutrophils interact with cholangiocytes to cause cholestatic changes in alcoholic hepatitis. Gut 2021;70:342-356. [PubMed: 33214166] 128.
  102. Li M, Mennone A, Soroka CJ, Hagey LR, Ouyang X, Weinman EJ, Boyer JL. Na(+)/H(+) exchanger regulatory factor 1 knockout mice have an attenuated hepatic inflammatory response and are protected from cholestatic liver injury. Hepatology 2015;62:1227-1236. [PubMed: 26108984] 129.
  103. Changho S, Ahmed AA. Neutrophils in biliary atresia. A study on their morphologic distribution and expression of CAP37. Pathol Res Pract 2010;206:314-317. [PubMed: 20399025] 130. Zhang R, Su L, Fu M, Wang Z, Tan L, Chen H, Lin Z, et al. CD177(+) cells produce neutrophil extracellular traps that promote biliary atresia. J Hepatol 2022;77:1299-1310. [PubMed: 35803543] 131. Thomson AW, O'Connell PJ, Steptoe RJ, Lu L. Immunobiology of liver dendritic cells. Immunol Cell Biol 2002;80:65-73. [PubMed: 11881616] 132. Weston CJ, Zimmermann HW, Adams DH. The Role of Myeloid-Derived Cells in the Progression of Liver Disease. Front Immunol 2019;10:893. [PubMed: 31068952] 133.
  104. Muller AL, Casar C, Preti M, Krzikalla D, Gottwick C, Averhoff P, Rosenstiel P, et al. Inflammatory type 2 conventional dendritic cells contribute to murine and human cholangitis. J Hepatol 2022;77:1532-1544. [PubMed: 35798133] 134.
  105. Katt J, Schwinge D, Schoknecht T, Quaas A, Sobottka I, Burandt E, Becker C, et al. Increased T helper type 17 response to pathogen stimulation in patients with primary sclerosing cholangitis. Hepatology 2013;58:1084-1093. [PubMed: 23564624] 135. Harada K, Shimoda S, Sato Y, Isse K, Ikeda H, Nakanuma Y. Periductal interleukin-17 production in association with biliary innate immunity contributes to the pathogenesis of cholangiopathy in primary biliary cirrhosis. Clin Exp Immunol 2009;157:261-270. [PubMed: 19604266] 136.
  106. Harada K, Shimoda S, Ikeda H, Chiba M, Hsu M, Sato Y, Kobayashi M, et al. Significance of periductal Langerhans cells and biliary epithelial cell-derived macrophage inflammatory protein-3alpha in the pathogenesis of primary biliary cirrhosis. Liver Int 2011;31:245-253. [PubMed: 21092071] 137.
  107. Flajnik MF, Kasahara M. Origin and evolution of the adaptive immune system: genetic events and selective pressures. Nat Rev Genet 2010;11:47-59. [PubMed: 19997068] 138.
  108. Chi H, Pepper M, Thomas PG. Principles and therapeutic applications of adaptive immunity. Cell 2024;187:2052-2078. [PubMed: 38670065] 139. Xanthopoulos A, Starling RC, Kitai T, Triposkiadis F. Heart Failure and Liver Disease: Cardiohepatic Interactions. JACC Heart Fail 2019;7:87-97. [PubMed: 30553904] 140. Racanelli V, Rehermann B. The liver as an immunological organ. Hepatology 2006;43:S54-62. [PubMed: 16447271] 141. Crispe IN. The liver as a lymphoid organ. Annu Rev Immunol 2009;27:147-163. [PubMed: 19302037] 142.
  109. Pallett LJ, Davies J, Colbeck EJ, Robertson F, Hansi N, Easom NJW, Burton AR, et al. IL-2(high) tissue-resident T cells in the human liver: Sentinels for hepatotropic infection. J Exp Med 2017;214:1567-1580. [PubMed: 28526759] 143.
  110. Stelma F, de Niet A, Sinnige MJ, van Dort KA, van Gisbergen K, Verheij J, van Leeuwen EMM, et al. Human intrahepatic CD69 + CD8+ T cells have a tissue resident memory T cell phenotype with reduced cytolytic capacity. Sci Rep 2017;7:6172. [PubMed: 28733665] 144.
  111. Liaskou E, Jeffery LE, Trivedi PJ, Reynolds GM, Suresh S, Bruns T, Adams DH, et al. Loss of CD28 expression by liver-infiltrating T cells contributes to pathogenesis of primary sclerosing cholangitis. Gastroenterology 2014;147:221-232 e227. [PubMed: 24726754] 145.
  112. Krams SM, Van de Water J, Coppel RL, Esquivel C, Roberts J, Ansari A, Gershwin ME. Analysis of hepatic T lymphocyte and immunoglobulin deposits in patients with primary biliary cirrhosis. Hepatology 1990;12:306-313. [PubMed: 2202637] 146.
  113. Lan RY, Cheng C, Lian ZX, Tsuneyama K, Yang GX, Moritoki Y, Chuang YH, et al. Liver- targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis. Hepatology 2006;43:729-737. [PubMed: 16557534] 147. Azad AI, Krishnan A, Troop L, Li Y, Katsumi T, Pavelko K, Kostallari E, et al. Targeted Apoptosis of Ductular Reactive Cells Reduces Hepatic Fibrosis in a Mouse Model of Cholestasis. Hepatology 2020;72:1013-1028. [PubMed: 32128842] 148.
  114. Oo YH, Banz V, Kavanagh D, Liaskou E, Withers DR, Humphreys E, Reynolds GM, et al. CXCR3-dependent recruitment and CCR6-mediated positioning of Th-17 cells in the inflamed liver. J Hepatol 2012;57:1044-1051. [PubMed: 22796894] 149.
  115. Isse K, Harada K, Zen Y, Kamihira T, Shimoda S, Harada M, Nakanuma Y. Fractalkine and CX3CR1 are involved in the recruitment of intraepithelial lymphocytes of intrahepatic bile ducts. Hepatology 2005;41:506-516. [PubMed: 15726664] 151.
  116. Heydtmann M, Lalor PF, Eksteen JA, Hubscher SG, Briskin M, Adams DH. CXC chemokine ligand 16 promotes integrin-mediated adhesion of liver-infiltrating lymphocytes to cholangiocytes and hepatocytes within the inflamed human liver. J Immunol 2005;174:1055- 1062. [PubMed: 15634930] 152. Jiang X, Bergquist A, Loscher BS, Venkatesh G, Mold JE, Holm K, Laerdahl JK, et al. A heterozygous germline CD100 mutation in a family with primary sclerosing cholangitis. Sci Transl Med 2021;13. 153.
  117. He Q, Lu Y, Tian W, Jiang R, Yu W, Liu Y, Sun M, et al. TOX deficiency facilitates the differentiation of IL-17A-producing gammadelta T cells to drive autoimmune hepatitis. Cell Mol Immunol 2022;19:1102-1116. [PubMed: 35986136] 155. Tang XZ, Jo J, Tan AT, Sandalova E, Chia A, Tan KC, Lee KH, et al. IL-7 licenses activation of human liver intrasinusoidal mucosal-associated invariant T cells. J Immunol 2013;190:3142- 3152. [PubMed: 23447689] 156.
  118. Webster KE, Kim HO, Kyparissoudis K, Corpuz TM, Pinget GV, Uldrich AP, Brink R, et al. IL-17-producing NKT cells depend exclusively on IL-7 for homeostasis and survival. Mucosal Immunol 2014;7:1058-1067. [PubMed: 24448098] 157.
  119. Stein S, Henze L, Poch T, Carambia A, Krech T, Preti M, Schuran FA, et al. IL-17A/F enable cholangiocytes to restrict T cell-driven experimental cholangitis by upregulating PD-L1 expression. J Hepatol 2021;74:919-930. [PubMed: 33197512] 158.
  120. Yamada G, Hyodo I, Tobe K, Mizuno M, Nishihara T, Kobayashi T, Nagashima H. Ultrastructural immunocytochemical analysis of lymphocytes infiltrating bile duct epithelia in primary biliary cirrhosis. Hepatology 1986;6:385-391. [PubMed: 2940162] 160. Zhao SX, Li WC, Fu N, Zhou GD, Liu SH, Jiang LN, Zhang YG, et al. Emperipolesis mediated by CD8(+) T cells correlates with biliary epithelia cell injury in primary biliary cholangitis. J Cell Mol Med 2020;24:1268-1275. [PubMed: 31851780] 161.
  121. Davies SP, Ronca V, Wootton GE, Krajewska NM, Bozward AG, Fiancette R, Patten DA, et al. Expression of E-cadherin by CD8(+) T cells promotes their invasion into biliary epithelial cells. Nat Commun 2024;15:853. [PubMed: 38286990] 162. Hsu HY, Chang MH, Ni YH, Huang SF. Cytomegalovirus infection and proinflammatory cytokine activation modulate the surface immune determinant expression and immunogenicity of cultured murine extrahepatic bile duct epithelial cells. Clin Exp Immunol 2001;126:84-91. [PubMed: 11678903] 163.
  122. Ayres RC, Neuberger JM, Shaw J, Joplin R, Adams DH. Intercellular adhesion molecule-1 and MHC antigens on human intrahepatic bile duct cells: effect of pro-inflammatory cytokines. Gut 1993;34:1245-1249. [PubMed: 8104850] 164.
  123. Cruickshank SM, Southgate J, Selby PJ, Trejdosiewicz LK. Expression and cytokine regulation of immune recognition elements by normal human biliary epithelial and established liver cell lines in vitro. J Hepatol 1998;29:550-558. [PubMed: 9824263] 165. Saidman SL, Duquesnoy RJ, Zeevi A, Fung JJ, Starzl TE, Demetris AJ. Recognition of major histocompatibility complex antigens on cultured human biliary epithelial cells by alloreactive lymphocytes. Hepatology 1991;13:239-246. [PubMed: 1704868] 166.
  124. Chapman RW, Kelly PM, Heryet A, Jewell DP, Fleming KA. Expression of HLA-DR antigens on bile duct epithelium in primary sclerosing cholangitis. Gut 1988;29:422-427. [PubMed: 3286382] 167. Berzins SP, Smyth MJ, Baxter AG. Presumed guilty: natural killer T cell defects and human disease. Nat Rev Immunol 2011;11:131-142. [PubMed: 21267014] 168. Constantinides MG, Belkaid Y. Early-life imprinting of unconventional T cells and tissue homeostasis. Science 2021;374:eabf0095. [PubMed: 34882451] 169.
  125. Provine NM, Klenerman P. MAIT Cells in Health and Disease. Annu Rev Immunol 2020;38:203- 228. [PubMed: 31986071] 170.
  126. Schrumpf E, Tan C, Karlsen TH, Sponheim J, Bjorkstrom NK, Sundnes O, Alfsnes K, et al. The biliary epithelium presents antigens to and activates natural killer T cells. Hepatology 2015;62:1249-1259. [PubMed: 25855031] 171. Jeffery HC, van Wilgenburg B, Kurioka A, Parekh K, Stirling K, Roberts S, Dutton EE, et al. Biliary epithelium and liver B cells exposed to bacteria activate intrahepatic MAIT cells through MR1. J Hepatol 2016;64:1118-1127. [PubMed: 26743076] 172.
  127. Xiao MH, Wu S, Liang P, Ma D, Zhang J, Chen H, Zhong Z, et al. Mucosal-associated invariant T cells promote ductular reaction through amphiregulin in biliary atresia. EBioMedicine 2024;103:105138. [PubMed: 38678809] 173. Elci BS, Nikolaev M, Rezakhani S, Lutolf MP. Bioengineered Tubular Biliary Organoids. Adv Healthc Mater 2024;13:e2302912. [PubMed: 38128045] 174.
  128. Shi S, Verstegen MMA, Roest HP, Ardisasmita AI, Cao W, Roos FJM, de Ruiter PE, et al. Recapitulating Cholangiopathy-Associated Necroptotic Cell Death In Vitro Using Human Cholangiocyte Organoids. Cell Mol Gastroenterol Hepatol 2022;13:541-564. [PubMed: 34700031] 175.
  129. Guicciardi ME, Krishnan A, Bronk SF, Hirsova P, Griffith TS, Gores GJ. Biliary tract instillation of a SMAC mimetic induces TRAIL-dependent acute sclerosing cholangitis-like injury in mice. Cell Death Dis 2017;8:e2535. [PubMed: 28055006] 176.
  130. Victorelli S, Salmonowicz H, Chapman J, Martini H, Vizioli MG, Riley JS, Cloix C, et al. Apoptotic stress causes mtDNA release during senescence and drives the SASP. Nature 2023;622:627-636. [PubMed: 37821702] 177.
  131. Guzior DV, Okros M, Shivel M, Armwald B, Bridges C, Fu Y, Martin C, et al. Bile salt hydrolase acyltransferase activity expands bile acid diversity. Nature 2024;626:852-858. [PubMed: 38326608] 178.
  132. Mohanty I, Mannochio-Russo H, Schweer JV, El Abiead Y, Bittremieux W, Xing S, Schmid R, et al. The underappreciated diversity of bile acid modifications. Cell 2024;187:1801-1818 e1820. [PubMed: 38471500] 179.
  133. Valestrand L, Zheng F, Hansen SH, Ogaard J, Hov JR, Bjorkstrom NK, Karlsen TH, et al. Bile from Patients with Primary Sclerosing Cholangitis Contains Mucosal-Associated Invariant T-Cell Antigens. Am J Pathol 2022;192:629-641. [PubMed: 35063408] 180.
  134. Seo DW, Choi HS, Lee SP, Kuver R. Oxysterols from human bile induce apoptosis of canine gallbladder epithelial cells in monolayer culture. Am J Physiol Gastrointest Liver Physiol 2004;287:G1247-1256. [PubMed: 15246959] 181. Hov JR, Karlsen TH. The microbiota and the gut-liver axis in primary sclerosing cholangitis. Nat Rev Gastroenterol Hepatol 2023;20:135-154. [PubMed: 36352157] 182.
  135. Nejman D, Livyatan I, Fuks G, Gavert N, Zwang Y, Geller LT, Rotter-Maskowitz A, et al. The human tumor microbiome is composed of tumor type-specific intracellular bacteria. Science 2020;368:973-980. [PubMed: 32467386] 183.
  136. Leinwand JC, Paul B, Chen R, Xu F, Sierra MA, Paluru MM, Nanduri S, et al. Intrahepatic microbes govern liver immunity by programming NKT cells. J Clin Invest 2022;132. 184. Collins SL, Stine JG, Bisanz JE, Okafor CD, Patterson AD. Bile acids and the gut microbiota: metabolic interactions and impacts on disease. Nat Rev Microbiol 2023;21:236-247. [PubMed: 36253479]

Authors
Jalan-Sakrikar, N., Guicciardi, M. E., O’Hara, S. P., Azad, A., LaRusso, N. F., Gores, G. J., & Huebert, R. C.
Affiliations
  • Department of Medicine, Division of Gastroenterology and Hepatology, Mayo College of Medicine and Science, Mayo Clinic, Rochester, Minnesota, USA
  • Mayo Clinic (US)
Corresponding author
Huebert, Robert C.
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2024-09-09
Volume
82
Issue
4
Pages
834-854
ISSN
  • 0270-9139 (ISSN-L)
  • 1527-3350
DOI
10.1097/hep.0000000000001093
PMC
PMC11890218
OpenAlex
W4402350544
Cited by
38
References
184
Citations by year
2026: 25 · 2025: 13
FWCI
2.73
Type
journal article
Language
en
Open access
Locations
  • Hepatology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
Funders
  • National Institutes of Health (DK084567, KL2TR002379)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK024031, R01DK124182, P30DK084567, R01DK057993, R01DK117861)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Surgery › Pediatric Hepatobiliary Diseases and Treatments
Keywords
cholangiocytes, cholestatic liver disease, cholangiopathy, senescence-associated secretory phenotype, hepatic stellate cells, bile duct inflammation, immune cell crosstalk, neutrophils, macrophages, T cells, B cells, cytokine and chemokine secretion, liver cirrhosis
MeSH terms
Animals, Bile Ducts, Cholestasis, Epithelial Cells, Humans

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