ROCK2 inhibition attenuates profibrogenic immune cell function to reverse thioacetamide-induced liver fibrosis
| العنوان: | ROCK2 inhibition attenuates profibrogenic immune cell function to reverse thioacetamide-induced liver fibrosis |
|---|---|
| المؤلفون: | Bruce R. Blazar, Gregory Miller, Wei Chen, Jing Liu, Melanie S. Nyuydzefe, Geoffrey R. Hill, Katharine M. Irvine, Michelle Melino, Wayne A. Schroder, Patrick Bertolino, Kelli P. A. MacDonald, Alexandra Zanin-Zhorov, Michele W.L. Teng, Christina Nalkurthi, Andrew D. Clouston |
| المصدر: | JHEP Reports |
| بيانات النشر: | Elsevier BV, 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | pSTAT3, phosphorylated signal transducer and activator of transcription, STAT3, signal transducer and activator of transcription 3, medicine.medical_treatment, AST, aspartate aminotransferase, TGF-β, transforming growth factor-beta, Chronic liver disease, TNF, tumour necrosis factor, RORγt, RAR-related orphan receptor gamma, Fibrosis, Th17, T helper 17, Immunology and Allergy, Macrophage, BMDM, bone marrow-derived macrophages, pCofilin, phosphorylated cofilin, Gastroenterology, qRT-PCR, quantitative real-time PCR, HSC, hepatic stellate cell, ECM, extracellular matrix, MMP, matrix metalloproteinase, IL-17, Cytokine, LPS, lipopolysaccharide, medicine.symptom, GC, germinal centre, ROCK2, Rho-associated kinase 2, Research Article, ROCK2 Inhibitor KD025, NASH, non-alcoholic steatohepatitis, Liver fibrosis, α-SMA, alpha smooth muscle actin, IHC, immunohistochemical, Tfh, T follicular helper, Inflammation, Col1a2, collagen type α1, Bcl6, B-cell lymphoma 6, ROCK2, Immune system, ALT, alanine aminotransferase, Internal Medicine, medicine, DR, ductular reaction, B cells, cGVHD, chronic graft-vs-host disease, pMac, peritoneal macrophages, TAA, thioacetamide, Hepatology, business.industry, Macrophages, SR, Sirius red, medicine.disease, ROCK, Rho-associated coiled-coil forming protein kinases, RAR, retinoic acid receptor, CLD, chronic liver disease, Cancer research, Therapy, HCC, hepatocellular carcinoma, business, Hepatic fibrosis |
| الوصف: | 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. Graphical abstract Highlights • ROCK2 inhibition with the small-molecule inhibitor KD025 prevents and reverses hepatoxin-induced liver fibrosis. • ROCK2 inhibition attenuates profibrogenic immune function. • KD025 exerts direct effects on liver macrophages resulting in decreased TNF secretion and impeded migration. • KD025 administration attenuates T cell IL-17 production and B-cell IgG production, which indirectly contributes to downregulation of profibrogenic macrophage function. |
| تدمد: | 2589-5559 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d909aee919cee8dee5b9a4e06674119fTest https://doi.org/10.1016/j.jhepr.2021.100386Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....d909aee919cee8dee5b9a4e06674119f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 25895559 |
|---|