Contrasting responses of Kupffer cells and inflammatory mononuclear phagocytes to biliary obstruction in a mouse model of cholestatic liver injury

Caroline C. Duwaerts, Stephan Gehring, Chao Wen Cheng, Nico van Rooijen, Stephen H. Gregory

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Background: Biliary obstruction and cholestasis are serious complications of many liver diseases. Although resident hepatic macrophages (Kupffer cells) are frequently implicated in disease progression, most studies fail to differentiate the contribution of Kupffer cells and inflammatory mononuclear phagocytes (iMNPs) that infiltrate the liver subsequent to obstruction. Aim: This study was undertaken to examine the roles and potential interactions of these two disparate mononuclear phagocyte populations in hepatic injury attending cholestasis. Methods: Female, C57Bl/6 mice were injected with magnetic beads on day 3 prior to sham operation or bile duct ligation (BDL) to facilitate subsequent Kupffer cell isolation. Three days post-surgery, animals were euthanized, and bead-containing Kupffer cells and iMNPs were separated, purified and analysed. To examine the ability of Kupffer cells to modulate iMNP activity, iMNPs were isolated from the livers of intact and Kupffer cell-depleted mice on day 3 post-surgery and compared. Results: Purified Kupffer cells and iMNP populations obtained from BDL mice exhibited heterogeneous morphologies rendering them visually indistinguishable. iMNPs, however, were characterized by the increased expression of Ly-6C and CD11b and the elevated production of chemokines/cytokines characteristic of inflammatory cells. In the absence of Kupffer cells, iMNPs immigrating to the liver following BDL exhibited significant decreases in CD11b and Ly-6C expression, and in pro-inflammatory chemokine/cytokine production. Conclusions: Kupffer cells and iMNPs exhibit disparate biological responses to biliary obstruction and cholestasis. Kupffer cells play a key role in regulating iMNP influx and activity.

Original languageEnglish
Pages (from-to)255-265
Number of pages11
JournalLiver International
Volume33
Issue number2
DOIs
Publication statusPublished - Feb 2013

Fingerprint

Kupffer Cells
Phagocytes
Liver
Wounds and Injuries
Cholestasis
Bile Ducts
Ligation
Chemokines
Cytokines
Cell Separation
Ambulatory Surgical Procedures
Population
Disease Progression
Liver Diseases
Macrophages

Keywords

  • Bile duct
  • Biliary obstruction
  • Inflammation
  • Liver
  • Macrophages

ASJC Scopus subject areas

  • Hepatology

Cite this

Contrasting responses of Kupffer cells and inflammatory mononuclear phagocytes to biliary obstruction in a mouse model of cholestatic liver injury. / Duwaerts, Caroline C.; Gehring, Stephan; Cheng, Chao Wen; van Rooijen, Nico; Gregory, Stephen H.

In: Liver International, Vol. 33, No. 2, 02.2013, p. 255-265.

Research output: Contribution to journalArticle

Duwaerts, Caroline C. ; Gehring, Stephan ; Cheng, Chao Wen ; van Rooijen, Nico ; Gregory, Stephen H. / Contrasting responses of Kupffer cells and inflammatory mononuclear phagocytes to biliary obstruction in a mouse model of cholestatic liver injury. In: Liver International. 2013 ; Vol. 33, No. 2. pp. 255-265.
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N2 - Background: Biliary obstruction and cholestasis are serious complications of many liver diseases. Although resident hepatic macrophages (Kupffer cells) are frequently implicated in disease progression, most studies fail to differentiate the contribution of Kupffer cells and inflammatory mononuclear phagocytes (iMNPs) that infiltrate the liver subsequent to obstruction. Aim: This study was undertaken to examine the roles and potential interactions of these two disparate mononuclear phagocyte populations in hepatic injury attending cholestasis. Methods: Female, C57Bl/6 mice were injected with magnetic beads on day 3 prior to sham operation or bile duct ligation (BDL) to facilitate subsequent Kupffer cell isolation. Three days post-surgery, animals were euthanized, and bead-containing Kupffer cells and iMNPs were separated, purified and analysed. To examine the ability of Kupffer cells to modulate iMNP activity, iMNPs were isolated from the livers of intact and Kupffer cell-depleted mice on day 3 post-surgery and compared. Results: Purified Kupffer cells and iMNP populations obtained from BDL mice exhibited heterogeneous morphologies rendering them visually indistinguishable. iMNPs, however, were characterized by the increased expression of Ly-6C and CD11b and the elevated production of chemokines/cytokines characteristic of inflammatory cells. In the absence of Kupffer cells, iMNPs immigrating to the liver following BDL exhibited significant decreases in CD11b and Ly-6C expression, and in pro-inflammatory chemokine/cytokine production. Conclusions: Kupffer cells and iMNPs exhibit disparate biological responses to biliary obstruction and cholestasis. Kupffer cells play a key role in regulating iMNP influx and activity.

AB - Background: Biliary obstruction and cholestasis are serious complications of many liver diseases. Although resident hepatic macrophages (Kupffer cells) are frequently implicated in disease progression, most studies fail to differentiate the contribution of Kupffer cells and inflammatory mononuclear phagocytes (iMNPs) that infiltrate the liver subsequent to obstruction. Aim: This study was undertaken to examine the roles and potential interactions of these two disparate mononuclear phagocyte populations in hepatic injury attending cholestasis. Methods: Female, C57Bl/6 mice were injected with magnetic beads on day 3 prior to sham operation or bile duct ligation (BDL) to facilitate subsequent Kupffer cell isolation. Three days post-surgery, animals were euthanized, and bead-containing Kupffer cells and iMNPs were separated, purified and analysed. To examine the ability of Kupffer cells to modulate iMNP activity, iMNPs were isolated from the livers of intact and Kupffer cell-depleted mice on day 3 post-surgery and compared. Results: Purified Kupffer cells and iMNP populations obtained from BDL mice exhibited heterogeneous morphologies rendering them visually indistinguishable. iMNPs, however, were characterized by the increased expression of Ly-6C and CD11b and the elevated production of chemokines/cytokines characteristic of inflammatory cells. In the absence of Kupffer cells, iMNPs immigrating to the liver following BDL exhibited significant decreases in CD11b and Ly-6C expression, and in pro-inflammatory chemokine/cytokine production. Conclusions: Kupffer cells and iMNPs exhibit disparate biological responses to biliary obstruction and cholestasis. Kupffer cells play a key role in regulating iMNP influx and activity.

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