Loss of myeloid related protein-8/14 exacerbates cardiac allograft rejection.
Loss of myeloid related protein-8/14 exacerbates cardiac allograft rejection.
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DOI：
10.1161/circulationaha.110.009910
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发表时间：
2011-12-20
期刊：
影响因子：
37.8
通讯作者：
Croce K
中科院分区：
文献类型：
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作者：
Shimizu K;Libby P;Rocha VZ;Folco EJ;Shubiki R;Grabie N;Jang S;Lichtman AH;Shimizu A;Hogg N;Simon DI;Mitchell RN;Croce K
钙结合蛋白骨髓相关蛋白 (MRP)-8 (S100A8) 和 MRP-14 (S100A9) 形成 MRP-8/14 异二聚体（S100A8/A9，钙卫蛋白），调节骨髓细胞功能和炎症反应，并作为监测急性同种异体移植排斥反应的早期血清标志物。尽管具有促炎介质的作用，但 MRP-8/14 复合物在心血管疾病中的病理生理学作用尚未完全确定。本研究使用缺乏 MRP-8/14 复合物的 MRP-14 缺陷小鼠 (MRP14-/-) 调查了 MRP-8/14 在心脏同种异体移植排斥中的作用。我们在野生型 (WT) 和 MRP14-/- 受者中检查了主要组织相容性复合体 (MHC) II 类异种不匹配心脏移植（bm12 供体心脏和 B6 受者）后的实质排斥 (PR)。 MRP14-/- 受者的同种异体移植物存活时间平均为 5.9 ± 2.9 周 (n=10)，而 WT 受者的同种异体移植物存活时间为 > 12 周 (n = 15，p < 0.0001)。移植后两周，MRP14-/- 受者的同种异体移植物的 PR 评分 (2.8 ± 0.8, n=8) 显着高于 WT 受者 (0.8 ± 0.8, n=12, p<0.0001)。与 WT 受者相比，MRP14-/- 受者的同种异体移植物的 T 细胞和巨噬细胞浸润显着增加，IFN-γ 和 IFN-γ 相关趋化因子（CXCL9、CXCL10 和 CXCL11）、IL-6 和 IL-17 的 mRNA 水平升高，Th17 细胞水平显着升高。 MRP14-/- 受者的邻近主动脉旁淋巴结中的淋巴细胞也明显多于 WT 受者（每个淋巴结的细胞数：MRP14-/- 为 23.7 ± 0.7 × 105，而 WT 为 6.0 ± 0.2 × 105，p < 0.0001）。移植后2周，bm12心脏的MRP14-/-受体的树突状细胞（DC）表达的共刺激分子CD80和CD86水平显着高于WT受体。使用同种异体 EC 引发的 MRP14-/- DC 进行的混合白细胞反应比使用 WT DC 的反应产生显着更高的抗原呈递功能。卵清蛋白引发的 MRP14-/- DC 增强了 OT-II CD4+ T 细胞的增殖，同时增加了 IL-2 和 IFN-γ 的产生。与来自转移的受体同种异体移植物的 WT DC 相比，B6 MHC II 类-/- 宿主和接受 MRP14-/- DC 的 B6 WT 宿主的心脏同种异体移植物显着增加了炎症细胞浸润并加速了同种异体移植排斥。与对照相比，感染 MRP-8 和 MRP-14 逆转录病毒载体的骨髓来源的 MRP14-/- DC 表现出 CD80 和 CD86 表达显着降低，表明 MRP-8/14 调节 B7 共刺激分子的表达。我们的结果表明，MRP-14 调节 B7 分子表达并减少 DC 的抗原呈递以及随后的 T 细胞启动。 MRP-14 的缺失显着增加了 T 细胞活化并加剧了同种异体移植排斥，表明 MRP-14 在免疫细胞生物学中以前未被认识到的作用。
The calcium-binding proteins myeloid-related protein (MRP)-8 (S100A8) and MRP-14 (S100A9) form MRP-8/14 heterodimers (S100A8/A9, calprotectin) that regulate myeloid cell function and inflammatory responses, and serve as early serum markers for monitoring acute allograft rejection. Despite functioning as a pro-inflammatory mediator, the pathophysiological role of MRP-8/14 complexes in cardiovascular disease is incompletely defined. This study investigated the role of MRP-8/14 in cardiac allograft rejection using MRP-14-deficient mice (MRP14-/-) that lack MRP-8/14 complexes. We examined parenchymal rejection (PR) after major histocompatibility complex (MHC) class II allomismatched cardiac transplantation (bm12 donor heart and B6 recipients) in wild-type (WT) and MRP14-/- recipients. Allograft survival averaged 5.9 ± 2.9 weeks (n=10) in MRP14-/- recipients, compared to > 12 weeks (n = 15, p < 0.0001) in WT recipients. Two weeks after transplantation, allografts in MRP14-/- recipients had significantly higher PR scores (2.8 ± 0.8, n=8) than did WT recipients (0.8 ± 0.8, n=12, p<0.0001). Compared to WT recipients, allografts in MRP14-/- recipients had significantly increased T-cell and macrophage infiltration, as well as increased mRNA levels of IFN-γ and IFN-γ–associated chemokines (CXCL9, CXCL10, and CXCL11), IL-6, and IL-17, with significantly higher levels of Th17 cells. MRP14-/- recipients also had significantly more lymphocytes in the adjacent paraaortic lymph nodes than did WT recipients (cell number per lymph node: 23.7 ± 0.7 × 105 for MRP14-/- vs. 6.0 ± 0.2 × 105 for WT, p < 0.0001). The dendritic cells (DCs) of the MRP14-/- recipients of bm12 hearts expressed significantly higher levels of the co-stimulatory molecules CD80 and CD86 than did those of WT recipients 2 weeks after transplantation. Mixed leukocyte reactions using allo-EC-primed MRP14-/- DCs resulted in significantly higher antigen-presenting function than reactions using WT DCs. Ovalbumin-primed MRP14-/- DCs augmented proliferation of OT-II CD4+ T cells with increased IL-2 and IFN-γ production. Cardiac allografts of B6 MHC class II-/- hosts and of B6 WT hosts receiving MRP14-/- DCs had significantly augmented inflammatory cell infiltration and accelerated allograft rejection, compared to WT DCs from transferred recipient allografts. Bone marrow–derived MRP14-/- DCs infected with MRP-8 and MRP-14 retroviral vectors showed significantly decreased CD80 and CD86 expression compared to controls, indicating that MRP-8/14 regulates B7-costimulatory molecule expression. Our results indicate that MRP-14 regulates B7 molecule expression and reduces antigen presentation by DCs, and subsequent T-cell priming. The absence of MRP-14 markedly increased T-cell activation and exacerbated allograft rejection, indicating a previously unrecognized role for MRP-14 in immune cell biology.