医学
促炎细胞因子
巨噬细胞极化
巨噬细胞
移植
免疫学
肿瘤坏死因子α
心脏移植
表型
癌症研究
炎症
内科学
生物
体外
生物化学
基因
作者
Yue Zhao,Song Chen,Peixiang Lan,Chenglin Wu,Dou Yu,Xiang Xiao,Zhiqiang Zhang,Laurie J. Minze,Xiaoshun He,Wenhao Chen,Xian Chang Li
摘要
Macrophages infiltrating the allografts are heterogeneous, consisting of proinflammatory (M1 cells) as well as antiinflammatory and fibrogenic phenotypes (M2 cells); they affect transplantation outcomes via diverse mechanisms. Here we found that macrophage polarization into M1 and M2 subsets was critically dependent on tumor necrosis factor receptor–associated factor 6 (TRAF6) and mammalian target of rapamycin (mTOR), respectively. In a heart transplant model we showed that macrophage-specific deletion of TRAF6 (LysMCreTraf6 fl/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 LysMCreTraf6 fl/fl recipients developed severe transplant vasculopathy (chronic rejection). The presentation of chronic rejection in CTLA4-Ig–treated LysMCreTraf6 fl/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 that 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 for preventing chronic allograft rejection, and that graft survival under such conditions is dependent on the PD-1/PD-L1 coinhibitory pathway. Macrophages infiltrating the allografts are heterogeneous, consisting of proinflammatory (M1 cells) as well as antiinflammatory and fibrogenic phenotypes (M2 cells); they affect transplantation outcomes via diverse mechanisms. Here we found that macrophage polarization into M1 and M2 subsets was critically dependent on tumor necrosis factor receptor–associated factor 6 (TRAF6) and mammalian target of rapamycin (mTOR), respectively. In a heart transplant model we showed that macrophage-specific deletion of TRAF6 (LysMCreTraf6 fl/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 LysMCreTraf6 fl/fl recipients developed severe transplant vasculopathy (chronic rejection). The presentation of chronic rejection in CTLA4-Ig–treated LysMCreTraf6 fl/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 that 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 for preventing chronic allograft rejection, and that graft survival under such conditions is dependent on the PD-1/PD-L1 coinhibitory pathway.
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