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      Activated cholangiocytes release macrophage-polarizing extracellular vesicles bearing the DAMP S100A11

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          In mouse models of biliary tract diseases, macrophages are recruited to the periductal milieu and promote injury and cholestasis. Although cell necrosis with release of biomolecules termed damage-associated molecular patterns (DAMPs) promotes recruitment and activation of macrophages, necrosis was not observed in these studies. Because extracellular vesicles (EVs) are important in cell-to-cell communication, we postulated that activated cholangiocytes may release EVs containing DAMPs as cargo. Both the human (NHC) and mouse cholangiocyte (603B) cell lines display constitutive activation with mRNA expression of chemokines. Proteomic analysis revealed that EVs from both cell lines contained the DAMP S100A11, a ligand for the receptor for advanced glycation end products (RAGE). Bone marrow-derived macrophages (BMDM) incubated with EVs derived from the mouse 603B cell line increased mRNA expression of proinflammatory cytokines. Genetic or pharmacologic inhibition of RAGE reduced BMDM expression of proinflammatory cytokines treated with EVs. RAGE signaling resulted in activation of the canonical NF-κB pathway, and consistently, proinflammatory cytokine expression was blunted by the IKKα/β inhibitor TPCA-1 in BMDM incubated with EVs. We also demonstrated that primary mouse cholangiocyte-derived organoids express chemokines indicating cholangiocyte activation, release EVs containing S100A11, and stimulate proinflammatory cytokine expression in BMDM by a RAGE-dependent pathway. In conclusion, these observations identify a non-cell death mechanism for cellular release of DAMPs by activated cholangiocytes, namely by releasing DAMPs as EV cargo. These data also suggest RAGE inhibitors may be salutary in macrophage-associated inflammatory diseases of the bile ducts.

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          Author and article information

          Am J Physiol Cell Physiol
          Am. J. Physiol., Cell Physiol
          Am J Physiol Cell Physiol
          American Journal of Physiology - Cell Physiology
          American Physiological Society (Bethesda, MD )
          1 October 2019
          31 July 2019
          1 October 2020
          : 317
          : 4
          : C788-C799
          Division of Gastroenterology and Hepatology and the Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic , Rochester, Michigan
          Author notes
          Address for reprint requests and other correspondence: G. J. Gores, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905 (e-mail: gores.gregory@ 123456mayo.edu ).
          PMC6851002 PMC6851002 6851002 C-00250-2019 C-00250-2019
          Copyright © 2019 the American Physiological Society
          Funded by: HHS | NIH | National Cancer Institute (NCI) 10.13039/100000054
          Award ID: CA15083-43C1
          Funded by: HHS | National Institutes of Health (NIH) 10.13039/100000002
          Award ID: DK084567
          Funded by: Chris M. Carlos and Catharine Nicole Jockisch Carlos Endowment in PSC
          Research Article


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