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

Tomohiro Katsumi, Maria Eugenia Guicciardi, Adiba Azad, Steven F. Bronk, Anuradha Krishnan, Gregory J. Gores

Research output: Contribution to journalArticle

1 Citation (Scopus)

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. 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.

Original languageEnglish (US)
Pages (from-to)C788-C799
JournalAmerican Journal of Physiology - Cell Physiology
Volume317
Issue number4
DOIs
StatePublished - Jan 1 2019

Fingerprint

Macrophages
Cytokines
Chemokines
Cell Line
Necrosis
Bile Duct Diseases
Organoids
Biliary Tract Diseases
Messenger RNA
Macrophage Activation
Extracellular Vesicles
Cholestasis
Cell Communication
Proteomics
Advanced Glycosylation End Product-Specific Receptor
Ligands
Wounds and Injuries

Keywords

  • Cholestatic liver injury
  • DAMPs
  • Extracellular vesicles
  • Macrophages
  • Sclerosing cholangitis

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

Cite this

Activated cholangiocytes release macrophage-polarizing extracellular vesicles bearing the DAMP S100A11. / Katsumi, Tomohiro; Guicciardi, Maria Eugenia; Azad, Adiba; Bronk, Steven F.; Krishnan, Anuradha; Gores, Gregory J.

In: American Journal of Physiology - Cell Physiology, Vol. 317, No. 4, 01.01.2019, p. C788-C799.

Research output: Contribution to journalArticle

Katsumi, Tomohiro ; Guicciardi, Maria Eugenia ; Azad, Adiba ; Bronk, Steven F. ; Krishnan, Anuradha ; Gores, Gregory J. / Activated cholangiocytes release macrophage-polarizing extracellular vesicles bearing the DAMP S100A11. In: American Journal of Physiology - Cell Physiology. 2019 ; Vol. 317, No. 4. pp. C788-C799.
@article{cab85facca6145eeb3fbe7afe46dda0b,
title = "Activated cholangiocytes release macrophage-polarizing extracellular vesicles bearing the DAMP S100A11",
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. 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.",
keywords = "Cholestatic liver injury, DAMPs, Extracellular vesicles, Macrophages, Sclerosing cholangitis",
author = "Tomohiro Katsumi and Guicciardi, {Maria Eugenia} and Adiba Azad and Bronk, {Steven F.} and Anuradha Krishnan and Gores, {Gregory J.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1152/ajpcell.00250.2019",
language = "English (US)",
volume = "317",
pages = "C788--C799",
journal = "American Journal of Physiology",
issn = "0363-6143",
publisher = "American Physiological Society",
number = "4",

}

TY - JOUR

T1 - Activated cholangiocytes release macrophage-polarizing extracellular vesicles bearing the DAMP S100A11

AU - Katsumi, Tomohiro

AU - Guicciardi, Maria Eugenia

AU - Azad, Adiba

AU - Bronk, Steven F.

AU - Krishnan, Anuradha

AU - Gores, Gregory J.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - Cholestatic liver injury

KW - DAMPs

KW - Extracellular vesicles

KW - Macrophages

KW - Sclerosing cholangitis

UR - http://www.scopus.com/inward/record.url?scp=85072717616&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85072717616&partnerID=8YFLogxK

U2 - 10.1152/ajpcell.00250.2019

DO - 10.1152/ajpcell.00250.2019

M3 - Article

C2 - 31365294

AN - SCOPUS:85072717616

VL - 317

SP - C788-C799

JO - American Journal of Physiology

JF - American Journal of Physiology

SN - 0363-6143

IS - 4

ER -