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ROCK2 inhibition attenuates profibrogenic immune cell function to reverse thioacetamide-induced liver fibrosis

BACKGROUND & AIMS: Fibrosis, the primary cause of morbidity in chronic liver disease, is induced by pro-inflammatory cytokines, immune cell infiltrates, and tissue resident cells that drive excessive myofibroblast activation, collagen production, and tissue scarring. Rho-associated kinase 2 (ROC...

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Autores principales: Nalkurthi, Christina, Schroder, Wayne A., Melino, Michelle, Irvine, Katharine M., Nyuydzefe, Melanie, Chen, Wei, Liu, Jing, Teng, Michele W.L., Hill, Geoffrey R., Bertolino, Patrick, Blazar, Bruce R., Miller, Gregory C., Clouston, Andrew D., Zanin-Zhorov, Alexandra, MacDonald, Kelli P.A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8645924/
https://www.ncbi.nlm.nih.gov/pubmed/34917911
http://dx.doi.org/10.1016/j.jhepr.2021.100386
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author Nalkurthi, Christina
Schroder, Wayne A.
Melino, Michelle
Irvine, Katharine M.
Nyuydzefe, Melanie
Chen, Wei
Liu, Jing
Teng, Michele W.L.
Hill, Geoffrey R.
Bertolino, Patrick
Blazar, Bruce R.
Miller, Gregory C.
Clouston, Andrew D.
Zanin-Zhorov, Alexandra
MacDonald, Kelli P.A.
author_facet Nalkurthi, Christina
Schroder, Wayne A.
Melino, Michelle
Irvine, Katharine M.
Nyuydzefe, Melanie
Chen, Wei
Liu, Jing
Teng, Michele W.L.
Hill, Geoffrey R.
Bertolino, Patrick
Blazar, Bruce R.
Miller, Gregory C.
Clouston, Andrew D.
Zanin-Zhorov, Alexandra
MacDonald, Kelli P.A.
author_sort Nalkurthi, Christina
collection PubMed
description BACKGROUND & AIMS: Fibrosis, the primary cause of morbidity in chronic liver disease, is induced by pro-inflammatory cytokines, immune cell infiltrates, and tissue resident cells that drive excessive myofibroblast activation, collagen production, and tissue scarring. Rho-associated kinase 2 (ROCK2) regulates key pro-fibrotic pathways involved in both inflammatory reactions and altered extracellular matrix remodelling, implicating this pathway as a potential therapeutic target. METHODS: We used the thioacetamide-induced liver fibrosis model to examine the efficacy of administration of the selective ROCK2 inhibitor KD025 to prevent or treat liver fibrosis and its impact on immune composition and function. RESULTS: Prophylactic and therapeutic administration of KD025 effectively attenuated thioacetamide-induced liver fibrosis and promoted fibrotic regression. KD025 treatment inhibited liver macrophage tumour necrosis factor production and disrupted the macrophage niche within fibrotic septae. ROCK2 targeting in vitro directly regulated macrophage function through disruption of signal transducer and activator of transcription 3 (STAT3)/cofilin signalling pathways leading to the inhibition of pro-inflammatory cytokine production and macrophage migration. In vivo, KDO25 administration significantly reduced STAT3 phosphorylation and cofilin levels in the liver. Additionally, livers exhibited robust downregulation of immune cell infiltrates and diminished levels of retinoic acid receptor-related orphan receptor gamma (RORγt) and B-cell lymphoma 6 (Bcl6) transcription factors that correlated with a significant reduction in liver IL-17, splenic germinal centre numbers and serum IgG. CONCLUSIONS: As IL-17 and IgG–Fc binding promote pathogenic macrophage differentiation, together our data demonstrate that ROCK2 inhibition prevents and reverses liver fibrosis through direct and indirect effects on macrophage function and highlight the therapeutic potential of ROCK2 inhibition in liver fibrosis. LAY SUMMARY: By using a clinic-ready small-molecule inhibitor, we demonstrate that selective ROCK2 inhibition prevents and reverses hepatic fibrosis through its pleiotropic effects on pro-inflammatory immune cell function. We show that ROCK2 mediates increased IL-17 production, antibody production, and macrophage dysregulation, which together drive fibrogenesis in a model of chemical-induced liver fibrosis. Therefore, in this study, we not only highlight the therapeutic potential of ROCK2 targeting in chronic liver disease but also provide previously undocumented insights into our understanding of cellular and molecular pathways driving the liver fibrosis pathology.
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spelling pubmed-86459242021-12-15 ROCK2 inhibition attenuates profibrogenic immune cell function to reverse thioacetamide-induced liver fibrosis Nalkurthi, Christina Schroder, Wayne A. Melino, Michelle Irvine, Katharine M. Nyuydzefe, Melanie Chen, Wei Liu, Jing Teng, Michele W.L. Hill, Geoffrey R. Bertolino, Patrick Blazar, Bruce R. Miller, Gregory C. Clouston, Andrew D. Zanin-Zhorov, Alexandra MacDonald, Kelli P.A. JHEP Rep Research Article BACKGROUND & AIMS: Fibrosis, the primary cause of morbidity in chronic liver disease, is induced by pro-inflammatory cytokines, immune cell infiltrates, and tissue resident cells that drive excessive myofibroblast activation, collagen production, and tissue scarring. Rho-associated kinase 2 (ROCK2) regulates key pro-fibrotic pathways involved in both inflammatory reactions and altered extracellular matrix remodelling, implicating this pathway as a potential therapeutic target. METHODS: We used the thioacetamide-induced liver fibrosis model to examine the efficacy of administration of the selective ROCK2 inhibitor KD025 to prevent or treat liver fibrosis and its impact on immune composition and function. RESULTS: Prophylactic and therapeutic administration of KD025 effectively attenuated thioacetamide-induced liver fibrosis and promoted fibrotic regression. KD025 treatment inhibited liver macrophage tumour necrosis factor production and disrupted the macrophage niche within fibrotic septae. ROCK2 targeting in vitro directly regulated macrophage function through disruption of signal transducer and activator of transcription 3 (STAT3)/cofilin signalling pathways leading to the inhibition of pro-inflammatory cytokine production and macrophage migration. In vivo, KDO25 administration significantly reduced STAT3 phosphorylation and cofilin levels in the liver. Additionally, livers exhibited robust downregulation of immune cell infiltrates and diminished levels of retinoic acid receptor-related orphan receptor gamma (RORγt) and B-cell lymphoma 6 (Bcl6) transcription factors that correlated with a significant reduction in liver IL-17, splenic germinal centre numbers and serum IgG. CONCLUSIONS: As IL-17 and IgG–Fc binding promote pathogenic macrophage differentiation, together our data demonstrate that ROCK2 inhibition prevents and reverses liver fibrosis through direct and indirect effects on macrophage function and highlight the therapeutic potential of ROCK2 inhibition in liver fibrosis. LAY SUMMARY: By using a clinic-ready small-molecule inhibitor, we demonstrate that selective ROCK2 inhibition prevents and reverses hepatic fibrosis through its pleiotropic effects on pro-inflammatory immune cell function. We show that ROCK2 mediates increased IL-17 production, antibody production, and macrophage dysregulation, which together drive fibrogenesis in a model of chemical-induced liver fibrosis. Therefore, in this study, we not only highlight the therapeutic potential of ROCK2 targeting in chronic liver disease but also provide previously undocumented insights into our understanding of cellular and molecular pathways driving the liver fibrosis pathology. Elsevier 2021-10-06 /pmc/articles/PMC8645924/ /pubmed/34917911 http://dx.doi.org/10.1016/j.jhepr.2021.100386 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Article
Nalkurthi, Christina
Schroder, Wayne A.
Melino, Michelle
Irvine, Katharine M.
Nyuydzefe, Melanie
Chen, Wei
Liu, Jing
Teng, Michele W.L.
Hill, Geoffrey R.
Bertolino, Patrick
Blazar, Bruce R.
Miller, Gregory C.
Clouston, Andrew D.
Zanin-Zhorov, Alexandra
MacDonald, Kelli P.A.
ROCK2 inhibition attenuates profibrogenic immune cell function to reverse thioacetamide-induced liver fibrosis
title ROCK2 inhibition attenuates profibrogenic immune cell function to reverse thioacetamide-induced liver fibrosis
title_full ROCK2 inhibition attenuates profibrogenic immune cell function to reverse thioacetamide-induced liver fibrosis
title_fullStr ROCK2 inhibition attenuates profibrogenic immune cell function to reverse thioacetamide-induced liver fibrosis
title_full_unstemmed ROCK2 inhibition attenuates profibrogenic immune cell function to reverse thioacetamide-induced liver fibrosis
title_short ROCK2 inhibition attenuates profibrogenic immune cell function to reverse thioacetamide-induced liver fibrosis
title_sort rock2 inhibition attenuates profibrogenic immune cell function to reverse thioacetamide-induced liver fibrosis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8645924/
https://www.ncbi.nlm.nih.gov/pubmed/34917911
http://dx.doi.org/10.1016/j.jhepr.2021.100386
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