A20 Haploinsufficiency Aggravates Transplant Arteriosclerosis in Mouse Vascular Allografts: Implications for Clinical Transplantation.
A20 Haploinsufficiency Aggravates Transplant Arteriosclerosis in Mouse Vascular Allografts: Implications for Clinical Transplantation.
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DOI：
10.1097/tp.0000000000001407
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发表时间：
2016-11
期刊：
影响因子：
6.2
通讯作者：
Ferran C
中科院分区：
文献类型：
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作者：
Moll HP;Lee A;Peterson CR;Revuelta Cervantes J;Wojcik BM;Parulkar A;Mele A;LoGerfo PJ;Siracuse JJ;Csizmadia E;da Silva CG;Ferran C
炎症是移植动脉硬化（TA）发病机制的核心。我们质疑抗炎A20的生理水平是否影响TA的严重程度。我们使用野生型（WT）或A20杂合子（HET）C57 BL/6（H-2b）供体和BALB/c（H-2d）受体，以及相反的BALB/c供体和WT/HET受体，进行了主要组织相容性复合体（MHC）不匹配的主动脉-颈动脉间置移植。我们通过组织学、免疫组织化学、免疫荧光和基因分析（qPCR）分析了主动脉同种异体移植物。我们在人和小鼠平滑肌细胞（SMC）培养物中验证了选择的体内A20靶标。我们注意到HET与WT同种异体移植物相比内膜增生显著更大，表明TA加重。移植后HET同种异体移植物中A20上调不足与NF-κB过度活化相关，通过较高水平的IκBα、p65、VCAM-1、ICAM-1、CXCL 10、CCL 2、TNF和IL-6（主要定位于SMC）来衡量。相应地，在人和小鼠SMC培养物中，马槟榔诱导的TNF和IL-6上调与A20表达呈负相关。HET与WT同种异体移植物中TA加重与内膜SMC增殖增加、浸润IFNγ+和颗粒酶B+ CD 4 + T细胞和自然杀伤细胞数量增加以及FoxP 3+调节性T细胞数量减少相关。A20单倍不足对TA无影响。同种异体血管移植物中A20单倍不足通过加重炎症、SMC增殖和致病性T细胞浸润而加重TA病变。A20单核苷酸多态性（SNP）与血管化同种异体移植物供体中A20表达或功能降低相关，可能会告知TA的风险和严重程度，突出了我们研究结果的临床意义。
Inflammation is central to the pathogenesis of transplant arteriosclerosis (TA). We questioned whether physiologic levels of anti-inflammatory A20 influence TA severity. We performed major histocompatibility complex (MHC) mismatched aorta to carotid artery interposition grafts, using wild type (WT) or A20 heterozygote (HET) C57BL/6 (H-2b) donors and BALB/c (H-2d) recipients, and conversely BALB/c donors and WT/HET recipients. We analyzed aortic allografts by histology, immunohistochemistry, immunofluorescence, and gene profiling (qPCR). We validated select in vivo A20 targets in human and mouse smooth muscle cell (SMC) cultures. We noted significantly greater intimal hyperplasia in HET vs. WT allografts, indicating aggravated TA. Inadequate upregulation of A20 in HET allografts after transplantation was associated with excessive NF-κB activation, gauged by higher levels of IκBα, p65, VCAM-1, ICAM-1, CXCL10, CCL2, TNF, and IL-6 (mostly localized to SMC). Correspondingly, cytokine-induced upregulation of TNF and IL-6 in human and mouse SMC cultures inversely correlated with A20 expression. Aggravated TA in HET vs. WT allografts correlated with increased intimal SMC proliferation, and a higher number of infiltrating IFNγ+ and Granzyme B+ CD4+ T cells and natural killer cells, and lower number of FoxP3+ regulatory T cells. A20 haploinsufficiency in allograft recipients did not influence TA. A20 haploinsufficiency in vascular allografts aggravates lesions of TA by exacerbating inflammation, SMC proliferation, and infiltration of pathogenic T cells. A20 single nucleotide polymorphisms (SNPs) associating with lower A20 expression or function in donors of vascularized allografts may inform risk and severity of TA, highlighting the clinical implications of our findings.