ECDI-fixed donor splenocytes prolong skin allograft survival by promoting M2 macrophage polarization and inducing regulatory T cells
ECDI-fixed donor splenocytes prolong skin allograft survival by promoting M2 macrophage polarization and inducing regulatory T cells
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ECDI™ 固定供体脾细胞通过促进 M2 巨噬细胞极化和诱导调节性 T 细胞延长皮肤同种异体移植物的存活
DOI：
10.1096/fba.2019-00029
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发表时间：
2019-11-01
影响因子：
2.7
通讯作者：
Zhuang，Ran
中科院分区：
文献类型：
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作者：
Zhou，Bo;Zhang，Yuan;Zhuang，Ran
排斥反应是同种异体组织移植的常见并发症。用1-乙基-3-（3 '-二甲基氨基丙基）-碳二亚胺（ECDI）固定脾细胞（SP）可诱导移植后受体的免疫耐受;然而，这种作用的机制尚不清楚。在这里，我们确定了ECDI-固定供体SP（ECDI-SP）诱导同种异体皮肤移植耐受的机制。与仅接受雷帕霉素治疗的小鼠相比，接受Balb/c全层皮肤移植的C57 BL/6受体小鼠沿着雷帕霉素输注两次供体来源的ECDI-SP，显示出上级皮肤同种异体移植物存活率和较低的炎性细胞浸润。在ECDI‐SP‐处理的小鼠中，血清中的抗炎细胞因子（如白细胞介素（IL）‐10）水平显著升高，而炎性细胞因子的表达显著抑制。脾脏巨噬细胞显著极化为替代活化巨噬细胞（M2）表型，脾脏和引流淋巴结中CD 4 + Foxp 3+调节性T细胞（TCFs）扩增。观察到ECDI-SP在体外的同种异体刺激活性和供体特异性离体低反应性。C57 BL/6巨噬细胞吞噬同种异体Balb/c衍生的ECDI-SP，极化为M2表型，具有明显的cAMP反应元件结合（CREB）蛋白磷酸化。通过促进IL-10表达的增加，ECDI-SP诱导M2极化和Treg产生，抑制效应T细胞增殖。因此，ECDI-SP通过增加CREB磷酸化和促进Treg产生来调节巨噬细胞M2极化以抑制同种异体皮肤移植物排斥。
Rejection is a common complication of allogeneic tissue transplantation. Fixation of splenocytes (SP) with 1‐ethyl‐3‐(3'‐dimethylaminopropyl)‐carbodiimide (ECDI) induces immune tolerance in recipients post‐transplantation; however, the mechanism underlying this effect remains unclear. Here, we determined the mechanisms of ECDI‐fixed donor SP (ECDI‐SP) in inducing tolerance in skin allograft transplantation. C57BL/6‐recipient mice that received Balb/c full‐thickness skin transplants with two infusions of donor‐derived ECDI‐SP, along with rapamycin showed superior skin allograft survival and lower inflammatory cell infiltration than mice that received rapamycin‐only treatment. In ECDI‐SP‐treated mice, the levels of anti‐inflammatory cytokines such as interleukin (IL)‐10 in sera were markedly increased, whereas the expression of inflammatory cytokines was significantly suppressed. Splenic macrophages were significantly polarized to the alternative activated macrophage (M2) phenotype, with expansion of CD4+Foxp3+regulatory T cells (Tregs) in the spleen and draining lymph nodes. Allostimulatory activity of ECDI‐SP in vitro and donor‐specific ex vivo hyporesponsiveness were observed. C57BL/6 macrophages engulfed allogeneic Balb/c‐derived ECDI‐SP, polarized to the M2 phenotype, with pronounced cAMP response element‐binding (CREB) protein phosphorylation. By facilitating increased IL‐10 expression, ECDI‐SP induced M2 polarization and Treg production, inhibiting effector T‐cell proliferation. Thus, ECDI‐SP modulates macrophage M2 polarization by increasing CREB phosphorylation and promoting Treg production to suppress allogeneic skin graft rejection.