Inhibition of intimal hyperplasia in murine aortic allografts by administration of a small-molecule TLR4 inhibitor TAK-242

Graft arteriosclerosis (GA) is the leading cause of late cardiac allograft dysfunction. The innate immune system plays a major role in GA, paprticularly Toll-like receptor 4 (TLR4) signaling. Here we characterized the role of TLR4 and its antagonist TAK-242 in a mouse model of GA. BALB/c (H-2d) dono...

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Bibliographic Details
Published in:Scientific reports 2017-11, Vol.7 (1), p.15799-11, Article 15799
Main Authors: Wu, Chuangyan, Ding, Xiangchao, Zhou, Cheng, Ye, Ping, Sun, Yuan, Wu, Jie, Zhang, Anchen, Huang, Xiaofan, Ren, Lingyun, Wang, Ke, Deng, Peng, Yue, Zhang, Chen, Jiuling, Wang, Sihua, Xia, Jiahong
Format: Article
Language:English
Subjects:
Allografts
Aorta
Arteriosclerosis
Bone marrow transplantation
Heart diseases
Heart transplantation
Histocompatibility antigen H-2
Hyperplasia
Immune system
Inflammation
Innate immunity
Interleukin 1
Leukocyte migration
Ly-6 antigen
Macrophages
Monocyte chemoattractant protein 1
Monocytes
Peripheral blood
Rodents
Skin & tissue grafts
Spleen
TLR4 protein
Toll-like receptors
Transplantation
γ-Interferon
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Summary:Graft arteriosclerosis (GA) is the leading cause of late cardiac allograft dysfunction. The innate immune system plays a major role in GA, paprticularly Toll-like receptor 4 (TLR4) signaling. Here we characterized the role of TLR4 and its antagonist TAK-242 in a mouse model of GA. BALB/c (H-2d) donor aortas were transplanted into C57BL/6 (H-2b) recipients, and the mice received intraperitoneal injection of 3 or 10 mg/kg of TAK-242 or vehicle every other day for 1, 2, 4, 6, 8 and 12 weeks. With TAK-242 administration, intimal hyperplasia initially appeared at 2 weeks after transplantation, and TAK-242 postponed the progression of neointimal formation in allogeneic aortic grafts. TAK-242 treatment reduced CD68+ macrophage accumulation in the allografts, reduced the levels of ly-6C monocytes in peripheral blood, bone marrow and spleen, and downregulated proinflammatory cytokine and chemokine levels. Ex vivo we observed that TAK-242 could improve the graft microenvironment by interfering the Tck/Mφ IL12p70 and IFNγ axis, reducing CCL2-mediated migration of vascular smooth cells.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-017-16160-4