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Wenru Su, Xiaoqing Chen, Yichen Xiao, Song Guo Zheng, Dan Liang; Caspase-8 Promotes Inflammation-Induced Lymphangiogenesis and Allograft Rejection in the Cornea. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2575.
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Graft rejection remains a major hurdle in transplantation medicine, and lymphangiogenesis plays a critical role in this process. An improved understanding of the mechanisms involved in graft rejection as well as new strategies to manage it are greatly needed. This study aimed to explore the clinical application of caspase inhibitors and the underlying molecular mechanisms in inflammation-induced lymphangiogenesis and graft rejection.
A mouse model of corneal transplantation and the RAW264.7 murine macrophage cell line was applied to investigate the underlying molecular mechanisms of ILA and graft rejection.
Corneal transplantation increased caspase-8 expression, and caspase-8 inhibition exerted substantial inhibitory effects on lymphangiogenesis, with significant decreases in the infiltration of macrophages and chemokines as well as the expression of vascular endothelial growth factor C (VEGF-C). In vitro, caspase-8 mediated Toll-like receptor 4 (TLR4)–dependent chemokines and VEGF-C production by macrophages. The knockout of TLR4 and the inhibition of high-mobility-group box-1 (HMGB1) signaling significantly inhibited lymphangiogenesis and caspase-8 activation after corneal transplantation, whereas a TLR4 agonist and recombinant HMGB1 promoted lymphangiogenesis and caspase-8 activation. Moreover, we found that caspase-8 regulated the activation of Nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome and HMGB1 secretion in macrophages and corneas after corneal transplantation. Importantly, topical caspase-8 inhibition significantly suppressed allograft rejection, with a major decrease in mature dendritic cells and Th17 cells in draining lymphoid nodes.
These findings provide the first demonstration that pharmacological inhibition of caspase-8 suppresses inflammatory lymphangiogenesis and allograft rejection; it supports the use of caspase-8 inhibition as a novel strategy for treating allograft rejection and lymphatic disorders.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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