3 years ago

Macrophage subpopulations and their impact on chronic allograft rejection versus graft acceptance in a mouse heart transplant model

Xian C. Li, Yue Zhao, Wenhao Chen, Xiaoshun He, Xiang Xiao, Peixiang Lan, Laurie Minze, Yaling Dou, Zhiqiang Zhang, Chenglin Wu, Song Chen
Macrophages infiltrating the allografts are heterogeneous, consisting of pro-inflammatory (M1 cells) as well as anti-inflammatory and fibrogenic phenotypes (M2 cells); they affect transplant outcomes via diverse mechanisms. Herein, we found that macrophage polarization into M1 and M2 subsets was critically dependent on TRAF6 and mTOR, respectively. In a heart transplant model we showed that macrophage-specific deletion of TRAF6 (LysMCreTraf6fl/fl) or mTOR (LysMCreMtorfl/fl) did not affect acute allograft rejection. However, treatment of LysMCreMtorfl/fl recipients with CTLA4-Ig induced long-term allograft survival (>100 days) without histological signs of chronic rejection, whereas the similarly treated LysMCreTraf6fl/fl recipients developed severe transplant vasculopathy (chronic rejection). The presentation of chronic rejection in CTLA4-Ig treated LysMCreTraf6fl/fl mice was similar to that of CTLA4-Ig treated wild type B6 recipients. Mechanistically, we found that the graft infiltrating macrophages in LysMCreMtorfl/fl recipients expressed high levels of PD-L1, and PD-L1 blockade readily induced rejection of otherwise survival grafts in the LysMCreMtorfl/fl recipients. Our findings demonstrate that targeting mTOR-dependent M2 cells is critical in preventing chronic allograft rejection and that graft survival under such conditions is dependent on the PD-1/PD-L1 co-inhibitory pathway. This article is protected by copyright. All rights reserved.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/ajt.14543

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