Antibody-induced vascular inflammation skews infiltrating macrophages to a novel remodeling phenotype in a model of transplant rejection.
Antibody-induced vascular inflammation skews infiltrating macrophages to a novel remodeling phenotype in a model of transplant rejection.
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DOI：
10.1111/ajt.15934
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发表时间：
2020-10
期刊：
影响因子：
--
通讯作者：
Reed EF
中科院分区：
文献类型：
--
作者：
Wei X;Valenzuela NM;Rossetti M;Sosa RA;Nevarez-Mejia J;Fishbein GA;Mulder A;Dhar J;Keslar KS;Baldwin WM 3rd;Fairchild RL;Hou J;Reed EF
HLA-donor specific antibodies (DSA) binding to vascular endothelial cells of the allograft trigger inflammation, vessel injury and antibody-mediated rejection (AMR). Accumulation of intragraft recipient macrophages is a histological characteristic of AMR, which portends worse outcome. HLA class I (HLA I) DSA enhance monocyte recruitment by activating endothelial cells and engaging FcγRs, but the DSA-activated donor endothelial influence on macrophage differentiation is unknown. In this study, we explored the consequence of DSA-activated endothelium on infiltrating monocyte differentiation. Here we show that cardiac allografts from murine recipients treated with MHC I DSA upregulated genes related to monocyte transmigration and Fc receptor stimulation. Human monocytes co-cultured with HLA I intact IgG- or F(ab’)2-stimulated primary human endothelium promoted monocyte differentiation into CD68+CD206+CD163+ macrophages (M(HLA I IgG)), while HLA I F(ab’)2-stimulated ECs solely induced higher CD206 (M(HLA I F(ab’)2)). Both macrophage subtypes exhibited significant changes in discrete cytokines/chemokines and unique gene expression profiles. Cross-comparison of gene transcripts between murine DSA-treated cardiac allografts and human co-cultured macrophages identified overlapping genes. These findings uncover the role of HLA I DSA-activated endothelium in monocyte differentiation, and point to a novel, remodeling phenotype of infiltrating macrophages that may contribute to vascular injury.
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