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

American Journal of Physiology. Cell Physiology
Tomohiro KatsumiGregory J Gores

Abstract

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....Continue Reading

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Citations

Mar 5, 2020·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Adiba I AzadGregory J Gores
Mar 19, 2021·Frontiers in Aging Neuroscience·Ewa SikoraJakub Wlodarczyk
Nov 2, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Daniel PrantnerStefanie N Vogel
Jun 5, 2021·Advanced Drug Delivery Reviews·Enis KostallariPierre-Emmanuel Rautou
Jun 16, 2021·Seminars in Liver Disease·Fernando BessoneMarcelo G Roma
Jun 29, 2021·Frontiers in Cell and Developmental Biology·Linqiang ZhangBin Liang

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Methods Mentioned

BETA
PCR
confocal microscopy
electron microscopy
transmission electron microscopy

Key Resources (RRID) Mentioned

AB_628017

Software Mentioned

GraphPad
GraphPad Prism

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