دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: ROCK2 inhibition attenuates profibrogenic immune cell function to reverse thioacetamide-induced liver fibrosis.
المؤلفون: Nalkurthi C; QIMR Berghofer Medical Research Institute, Brisbane, Australia.; The University of Queensland, Brisbane, QLD, Australia., Schroder WA; QIMR Berghofer Medical Research Institute, Brisbane, Australia., Melino M; QIMR Berghofer Medical Research Institute, Brisbane, Australia., Irvine KM; Mater Research, Translational Research Institute, University of Queensland, Brisbane, Australia., Nyuydzefe M; Kadmon Corporation LLC, New York, NY, USA., Chen W; Kadmon Corporation LLC, New York, NY, USA., Liu J; QIMR Berghofer Medical Research Institute, Brisbane, Australia., Teng MWL; QIMR Berghofer Medical Research Institute, Brisbane, Australia., Hill GR; Clinical Research Division, Fred Hutchinson Cancer Research Centre, Seattle, WA, USA., Bertolino P; Centenary Institute, Sydney, Australia., Blazar BR; Masonic Cancer Center and Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA., Miller GC; Envoi Specialist Pathologists, Brisbane, Australia., Clouston AD; Envoi Specialist Pathologists, Brisbane, Australia., Zanin-Zhorov A; Equilibre BioPharmaceuticals LLC, New York, NY, USA., MacDonald KPA; QIMR Berghofer Medical Research Institute, Brisbane, Australia.
المصدر: JHEP reports : innovation in hepatology [JHEP Rep] 2021 Oct 06; Vol. 4 (1), pp. 100386. Date of Electronic Publication: 2021 Oct 06 (Print Publication: 2022).
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier B.V Country of Publication: Netherlands NLM ID: 101761237 Publication Model: eCollection Cited Medium: Internet ISSN: 2589-5559 (Electronic) Linking ISSN: 25895559 NLM ISO Abbreviation: JHEP Rep Subsets: PubMed not MEDLINE
أسماء مطبوعة: Original Publication: [Amsterdam] : Elsevier B.V., [2019]-
مستخلص: 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.
Competing Interests: The authors declare no competing financial interests. BRB receives remuneration as an advisor to Magenta Therapeutics and BlueRock Therapeutics; received research funding from BlueRock Therapeutics, Rheos Medicines, Childrens' Cancer Research Fund, and KidsFirst Fund; and is a co-founder of Tmunity. MN, WC, and AZZ are full-time employees of Kadmon Pharmaceuticals, LLC. Please refer to the accompanying ICMJE disclosure forms for further details.
(© 2021 The Authors.)
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معلومات مُعتمدة: P01 AI056299 United States AI NIAID NIH HHS
فهرسة مساهمة: Keywords: ALT, alanine aminotransferase; AST, aspartate aminotransferase; B cells; BMDM, bone marrow-derived macrophages; Bcl6, B-cell lymphoma 6; CLD, chronic liver disease; Col1a2, collagen type α1; DR, ductular reaction; ECM, extracellular matrix; GC, germinal centre; HCC, hepatocellular carcinoma; HSC, hepatic stellate cell; IHC, immunohistochemical; IL-17; Inflammation; LPS, lipopolysaccharide; Liver fibrosis; MMP, matrix metalloproteinase; Macrophages; NASH, non-alcoholic steatohepatitis; RAR, retinoic acid receptor; ROCK, Rho-associated coiled-coil forming protein kinases; ROCK2; ROCK2, Rho-associated kinase 2; RORγt, RAR-related orphan receptor gamma; SR, Sirius red; STAT3, signal transducer and activator of transcription 3; TAA, thioacetamide; TGF-β, transforming growth factor-beta; TNF, tumour necrosis factor; Tfh, T follicular helper; Th17, T helper 17; Therapy; cGVHD, chronic graft-vs-host disease; pCofilin, phosphorylated cofilin; pMac, peritoneal macrophages; pSTAT3, phosphorylated signal transducer and activator of transcription; qRT-PCR, quantitative real-time PCR; α-SMA, alpha smooth muscle actin
تواريخ الأحداث: Date Created: 20211217 Latest Revision: 20220512
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC8645924
DOI: 10.1016/j.jhepr.2021.100386
PMID: 34917911
قاعدة البيانات: MEDLINE
الوصف
تدمد:2589-5559
DOI:10.1016/j.jhepr.2021.100386