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Toll-like receptor 3 is an endogenous sensor of cell death and a potential target for induction of long-term cardiac transplant survival.
Zhao, Jiangqi; Huang, Xuyan; Mcleod, Patrick; Jiang, Jifu; Liu, Winnie; Haig, Aaron; Jevnikar, Anthony M; Jiang, Zhenyu; Zhang, Zhu-Xu.
Afiliação
  • Zhao J; Department of Rheumatology and Immunology, The First Hospital of Jilin University, Changchun, China.
  • Huang X; Department of Pathology, Western University, London, ON, Canada.
  • Mcleod P; Matthew Mailing Centre for Translational Transplantation Studies, London, ON, Canada.
  • Jiang J; Matthew Mailing Centre for Translational Transplantation Studies, London, ON, Canada.
  • Liu W; Matthew Mailing Centre for Translational Transplantation Studies, London, ON, Canada.
  • Haig A; Matthew Mailing Centre for Translational Transplantation Studies, London, ON, Canada.
  • Jevnikar AM; Multi-Organ Transplant Program, London Health Sciences Centre, London, ON, Canada.
  • Jiang Z; Department of Pathology, Western University, London, ON, Canada.
  • Zhang ZX; Department of Pathology, Western University, London, ON, Canada.
Am J Transplant ; 21(10): 3268-3279, 2021 10.
Article em En | MEDLINE | ID: mdl-33784431
Inflammation posttransplant is directly linked to cell death programs including apoptosis and necrosis. Cell death leads to the release of cellular contents which can promote inflammation. Targeting of these pathways should be an effective strategy to prevent transplant rejection. Toll-like receptor 3 (TLR3) is emerging as a major endogenous sensor of inflammation. In this study, we assessed the role of TLR3 on cell death and transplant rejection. We showed that TLR3 is highly expressed on mouse microvascular endothelial cell (ECs) and the endothelium of cardiac grafts. We demonstrated that TLR3 interacting with dsRNA or self-RNA triggered apoptosis and necroptosis in ECs. Interestingly, TLR3-induced necroptosis led mitochondrial damage. Inhibition of the mitochondrial membrane permeability molecule Cyclophilin D prevented necroptosis in ECs. In vivo, endothelium damage and activities of caspase-3 and mixed lineage kinase domain-like protein were inhibited in TLR3-/- cardiac grafts compared with C57BL/6 grafts posttransplant (n = 5, p < .001). Importantly, TLR3-/- cardiac grafts had prolonged survival in allogeneic BALB/c mice (mean survival = 121 ± 67 vs. 31 ± 6 days of C57BL/6 grafts, n = 7, p = .002). In summary, our study suggests that TLR3 is an important cell death inducer in ECs and cardiac grafts and thus a potential therapeutic target in preventing cardiac transplant rejection.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transplante de Coração / Receptor 3 Toll-Like Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Am J Transplant Assunto da revista: TRANSPLANTE Ano de publicação: 2021 Tipo de documento: Article País de afiliação: China

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transplante de Coração / Receptor 3 Toll-Like Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Am J Transplant Assunto da revista: TRANSPLANTE Ano de publicação: 2021 Tipo de documento: Article País de afiliação: China