Macrophages contribute to the pathogenesis of sclerosing cholangitis in mice

Maria Eugenia Guicciardi, Christy E. Trussoni, Anuradha Krishnan, Steven F. Bronk, Maria J. Lorenzo Pisarello, Steven P. O'Hara, Patrick L. Splinter, Yandong Gao, Pamela Vig, Alexander Revzin, Nicholas F La Russo, Gregory James Gores

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Background & Aims: Macrophages contribute to liver disease, but their role in cholestatic liver injury, including primary sclerosing cholangitis (PSC), is unclear. We tested the hypothesis that macrophages contribute to the pathogenesis of, and are therapeutic targets for, PSC. Methods: Immune cell profile, hepatic macrophage number, localization and polarization, fibrosis, and serum markers of liver injury and cholestasis were measured in an acute (intrabiliary injection of the inhibitor of apoptosis antagonist BV6) and chronic (Mdr2−/− mice) mouse model of sclerosing cholangitis (SC). Selected observations were confirmed in liver specimens from patients with PSC. Because of the known role of the CCR2/CCL2 axis in monocyte/macrophage chemotaxis, therapeutic effects of the CCR2/5 antagonist cenicriviroc (CVC), or genetic deletion of CCR2 (Ccr2−/− mice) were determined in BV6-injected mice. Results: We found increased peribiliary pro-inflammatory (M1-like) and alternatively-activated (M2-like) monocyte-derived macrophages in PSC compared to normal livers. In both SC models, genetic profiling of liver immune cells identified a predominance of monocytes/macrophages; immunohistochemistry confirmed peribiliary monocyte-derived macrophage recruitment (M1>M2-polarized), which paralleled injury onset and was reversed upon resolution in acute SC mice. PSC, senescent and BV6-treated human cholangiocytes released monocyte chemoattractants (CCL2, IL-8) and macrophage-activating factors in vitro. Pharmacological inhibition of monocyte recruitment by CVC treatment or CCR2 genetic deletion attenuated macrophage accumulation, liver injury and fibrosis in acute SC. Conclusions: Peribiliary recruited macrophages are a feature of both PSC and acute and chronic murine SC models. Pharmacologic and genetic inhibition of peribiliary macrophage recruitment decreases liver injury and fibrosis in mouse SC. These observations suggest monocyte-derived macrophages contribute to the development of SC in mice and in PSC pathogenesis, and support their potential as a therapeutic target. Lay summary: Primary sclerosing cholangitis (PSC) is an inflammatory liver disease which often progresses to liver failure. The cause of the disease is unclear and therapeutic options are limited. Therefore, we explored the role of white blood cells termed macrophages in PSC given their frequent contribution to other human inflammatory diseases. Our results implicate macrophages in PSC and PSC-like diseases in mice. More importantly, we found that pharmacologic inhibition of macrophage recruitment to the liver reduces PSC-like liver injury in the mouse. These exciting observations highlight potential new strategies to treat PSC.

Original languageEnglish (US)
JournalJournal of Hepatology
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Sclerosing Cholangitis
Macrophages
Liver
Monocytes
Wounds and Injuries
Liver Cirrhosis
Liver Diseases
Macrophage-Activating Factors

Keywords

  • C-C chemokine ligand 2 (CCL2)
  • C-C chemokine receptor 2 (CCR2)
  • Cenicriviroc (CVC)
  • Cholestatic liver injury
  • Liver fibrosis
  • Macrophages
  • Sclerosing cholangitis

ASJC Scopus subject areas

  • Hepatology

Cite this

Guicciardi, M. E., Trussoni, C. E., Krishnan, A., Bronk, S. F., Lorenzo Pisarello, M. J., O'Hara, S. P., ... Gores, G. J. (Accepted/In press). Macrophages contribute to the pathogenesis of sclerosing cholangitis in mice. Journal of Hepatology. https://doi.org/10.1016/j.jhep.2018.05.018

Macrophages contribute to the pathogenesis of sclerosing cholangitis in mice. / Guicciardi, Maria Eugenia; Trussoni, Christy E.; Krishnan, Anuradha; Bronk, Steven F.; Lorenzo Pisarello, Maria J.; O'Hara, Steven P.; Splinter, Patrick L.; Gao, Yandong; Vig, Pamela; Revzin, Alexander; La Russo, Nicholas F; Gores, Gregory James.

In: Journal of Hepatology, 01.01.2018.

Research output: Contribution to journalArticle

Guicciardi, ME, Trussoni, CE, Krishnan, A, Bronk, SF, Lorenzo Pisarello, MJ, O'Hara, SP, Splinter, PL, Gao, Y, Vig, P, Revzin, A, La Russo, NF & Gores, GJ 2018, 'Macrophages contribute to the pathogenesis of sclerosing cholangitis in mice', Journal of Hepatology. https://doi.org/10.1016/j.jhep.2018.05.018
Guicciardi ME, Trussoni CE, Krishnan A, Bronk SF, Lorenzo Pisarello MJ, O'Hara SP et al. Macrophages contribute to the pathogenesis of sclerosing cholangitis in mice. Journal of Hepatology. 2018 Jan 1. https://doi.org/10.1016/j.jhep.2018.05.018
Guicciardi, Maria Eugenia ; Trussoni, Christy E. ; Krishnan, Anuradha ; Bronk, Steven F. ; Lorenzo Pisarello, Maria J. ; O'Hara, Steven P. ; Splinter, Patrick L. ; Gao, Yandong ; Vig, Pamela ; Revzin, Alexander ; La Russo, Nicholas F ; Gores, Gregory James. / Macrophages contribute to the pathogenesis of sclerosing cholangitis in mice. In: Journal of Hepatology. 2018.
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abstract = "Background & Aims: Macrophages contribute to liver disease, but their role in cholestatic liver injury, including primary sclerosing cholangitis (PSC), is unclear. We tested the hypothesis that macrophages contribute to the pathogenesis of, and are therapeutic targets for, PSC. Methods: Immune cell profile, hepatic macrophage number, localization and polarization, fibrosis, and serum markers of liver injury and cholestasis were measured in an acute (intrabiliary injection of the inhibitor of apoptosis antagonist BV6) and chronic (Mdr2−/− mice) mouse model of sclerosing cholangitis (SC). Selected observations were confirmed in liver specimens from patients with PSC. Because of the known role of the CCR2/CCL2 axis in monocyte/macrophage chemotaxis, therapeutic effects of the CCR2/5 antagonist cenicriviroc (CVC), or genetic deletion of CCR2 (Ccr2−/− mice) were determined in BV6-injected mice. Results: We found increased peribiliary pro-inflammatory (M1-like) and alternatively-activated (M2-like) monocyte-derived macrophages in PSC compared to normal livers. In both SC models, genetic profiling of liver immune cells identified a predominance of monocytes/macrophages; immunohistochemistry confirmed peribiliary monocyte-derived macrophage recruitment (M1>M2-polarized), which paralleled injury onset and was reversed upon resolution in acute SC mice. PSC, senescent and BV6-treated human cholangiocytes released monocyte chemoattractants (CCL2, IL-8) and macrophage-activating factors in vitro. Pharmacological inhibition of monocyte recruitment by CVC treatment or CCR2 genetic deletion attenuated macrophage accumulation, liver injury and fibrosis in acute SC. Conclusions: Peribiliary recruited macrophages are a feature of both PSC and acute and chronic murine SC models. Pharmacologic and genetic inhibition of peribiliary macrophage recruitment decreases liver injury and fibrosis in mouse SC. These observations suggest monocyte-derived macrophages contribute to the development of SC in mice and in PSC pathogenesis, and support their potential as a therapeutic target. Lay summary: Primary sclerosing cholangitis (PSC) is an inflammatory liver disease which often progresses to liver failure. The cause of the disease is unclear and therapeutic options are limited. Therefore, we explored the role of white blood cells termed macrophages in PSC given their frequent contribution to other human inflammatory diseases. Our results implicate macrophages in PSC and PSC-like diseases in mice. More importantly, we found that pharmacologic inhibition of macrophage recruitment to the liver reduces PSC-like liver injury in the mouse. These exciting observations highlight potential new strategies to treat PSC.",
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T1 - Macrophages contribute to the pathogenesis of sclerosing cholangitis in mice

AU - Guicciardi, Maria Eugenia

AU - Trussoni, Christy E.

AU - Krishnan, Anuradha

AU - Bronk, Steven F.

AU - Lorenzo Pisarello, Maria J.

AU - O'Hara, Steven P.

AU - Splinter, Patrick L.

AU - Gao, Yandong

AU - Vig, Pamela

AU - Revzin, Alexander

AU - La Russo, Nicholas F

AU - Gores, Gregory James

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Background & Aims: Macrophages contribute to liver disease, but their role in cholestatic liver injury, including primary sclerosing cholangitis (PSC), is unclear. We tested the hypothesis that macrophages contribute to the pathogenesis of, and are therapeutic targets for, PSC. Methods: Immune cell profile, hepatic macrophage number, localization and polarization, fibrosis, and serum markers of liver injury and cholestasis were measured in an acute (intrabiliary injection of the inhibitor of apoptosis antagonist BV6) and chronic (Mdr2−/− mice) mouse model of sclerosing cholangitis (SC). Selected observations were confirmed in liver specimens from patients with PSC. Because of the known role of the CCR2/CCL2 axis in monocyte/macrophage chemotaxis, therapeutic effects of the CCR2/5 antagonist cenicriviroc (CVC), or genetic deletion of CCR2 (Ccr2−/− mice) were determined in BV6-injected mice. Results: We found increased peribiliary pro-inflammatory (M1-like) and alternatively-activated (M2-like) monocyte-derived macrophages in PSC compared to normal livers. In both SC models, genetic profiling of liver immune cells identified a predominance of monocytes/macrophages; immunohistochemistry confirmed peribiliary monocyte-derived macrophage recruitment (M1>M2-polarized), which paralleled injury onset and was reversed upon resolution in acute SC mice. PSC, senescent and BV6-treated human cholangiocytes released monocyte chemoattractants (CCL2, IL-8) and macrophage-activating factors in vitro. Pharmacological inhibition of monocyte recruitment by CVC treatment or CCR2 genetic deletion attenuated macrophage accumulation, liver injury and fibrosis in acute SC. Conclusions: Peribiliary recruited macrophages are a feature of both PSC and acute and chronic murine SC models. Pharmacologic and genetic inhibition of peribiliary macrophage recruitment decreases liver injury and fibrosis in mouse SC. These observations suggest monocyte-derived macrophages contribute to the development of SC in mice and in PSC pathogenesis, and support their potential as a therapeutic target. Lay summary: Primary sclerosing cholangitis (PSC) is an inflammatory liver disease which often progresses to liver failure. The cause of the disease is unclear and therapeutic options are limited. Therefore, we explored the role of white blood cells termed macrophages in PSC given their frequent contribution to other human inflammatory diseases. Our results implicate macrophages in PSC and PSC-like diseases in mice. More importantly, we found that pharmacologic inhibition of macrophage recruitment to the liver reduces PSC-like liver injury in the mouse. These exciting observations highlight potential new strategies to treat PSC.

AB - Background & Aims: Macrophages contribute to liver disease, but their role in cholestatic liver injury, including primary sclerosing cholangitis (PSC), is unclear. We tested the hypothesis that macrophages contribute to the pathogenesis of, and are therapeutic targets for, PSC. Methods: Immune cell profile, hepatic macrophage number, localization and polarization, fibrosis, and serum markers of liver injury and cholestasis were measured in an acute (intrabiliary injection of the inhibitor of apoptosis antagonist BV6) and chronic (Mdr2−/− mice) mouse model of sclerosing cholangitis (SC). Selected observations were confirmed in liver specimens from patients with PSC. Because of the known role of the CCR2/CCL2 axis in monocyte/macrophage chemotaxis, therapeutic effects of the CCR2/5 antagonist cenicriviroc (CVC), or genetic deletion of CCR2 (Ccr2−/− mice) were determined in BV6-injected mice. Results: We found increased peribiliary pro-inflammatory (M1-like) and alternatively-activated (M2-like) monocyte-derived macrophages in PSC compared to normal livers. In both SC models, genetic profiling of liver immune cells identified a predominance of monocytes/macrophages; immunohistochemistry confirmed peribiliary monocyte-derived macrophage recruitment (M1>M2-polarized), which paralleled injury onset and was reversed upon resolution in acute SC mice. PSC, senescent and BV6-treated human cholangiocytes released monocyte chemoattractants (CCL2, IL-8) and macrophage-activating factors in vitro. Pharmacological inhibition of monocyte recruitment by CVC treatment or CCR2 genetic deletion attenuated macrophage accumulation, liver injury and fibrosis in acute SC. Conclusions: Peribiliary recruited macrophages are a feature of both PSC and acute and chronic murine SC models. Pharmacologic and genetic inhibition of peribiliary macrophage recruitment decreases liver injury and fibrosis in mouse SC. These observations suggest monocyte-derived macrophages contribute to the development of SC in mice and in PSC pathogenesis, and support their potential as a therapeutic target. Lay summary: Primary sclerosing cholangitis (PSC) is an inflammatory liver disease which often progresses to liver failure. The cause of the disease is unclear and therapeutic options are limited. Therefore, we explored the role of white blood cells termed macrophages in PSC given their frequent contribution to other human inflammatory diseases. Our results implicate macrophages in PSC and PSC-like diseases in mice. More importantly, we found that pharmacologic inhibition of macrophage recruitment to the liver reduces PSC-like liver injury in the mouse. These exciting observations highlight potential new strategies to treat PSC.

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KW - C-C chemokine receptor 2 (CCR2)

KW - Cenicriviroc (CVC)

KW - Cholestatic liver injury

KW - Liver fibrosis

KW - Macrophages

KW - Sclerosing cholangitis

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