PDF(Pubmed)
Abstract：
Objective: Chronic rejection remains the main factor that influence long-term survival of patients after heart transplantation. Interleukin-10 (IL-10) play critical role in macrophages-mediated transplant immune responses. We investigated the mechanism of IL-10 in macrophage related chronic rejection after mouse heart transplantation. Methods: Mouse heart transplant chronic rejection model was established to evaluate pathological changes in the allograft. Myocardial interstitial fibrosis, apoptosis, and inflammatory factor levels were detected in ad-IL-10-treated mice. The positive iNOS+ and Arg-1+ expressions, macrophage subset changes, and the proportion of regulatory T-cells (Tregs) and TIGIT+ Tregs were quantified by flow. In in vitro experiments, ad-IL-10 was transfected into macrophages followed by detection of apoptosis, phagocytosis, and CD163, CD16/32, and CD206 expression. The expression and relationships between IL-10, miR-155, and SOCS5 were also detected and verified. A rescue experiment was performed to evaluate macrophage function through the combined treatment of ad-IL-10 and overexpression of miR-155. Results: Significantly decreased IL-10 expression in chronic rejection during mouse heart transplantation was observed. Ad-IL-10-treated mice showed decreased pathological injury, perivascular fibrosis, apoptosis, inflammation, and iNOS+ and CD16/32+ expression, and increased Treg/TIGIT+ Treg cell, Arg-1+ and CD206+ cell proportion. Ad-IL-10-treated macrophages in vitro showed reduced apoptosis, improved phagocytosis, and M2 polarization. Mechanically, IL-10 negatively regulated miR-155 to activate SOCS5. Overexpression of miR-155 reversed IL-10 mediated-positive regulation of macrophage function. Conclusion: IL-10 downregulated miR-155 and activated SOCS5, thereby promoting macrophage M2 polarization to relieve chronic rejection after heart transplantation.
摘要：
目的:慢性排斥反应是影响心脏移植术后患者长期生存的主要因素。白细胞介素-10(IL-10)在巨噬细胞介导的移植免疫应答中起关键作用。我们研究了IL-10在小鼠心脏移植后巨噬细胞相关慢性排斥反应中的作用机制。方法：建立小鼠心脏移植慢性排斥反应模型，评价同种异体移植的病理变化。心肌间质纤维化,凋亡，在ad-IL-10处理的小鼠中检测到炎症因子水平。iNOS+和Arg-1+阳性表达,巨噬细胞亚群变化，并且通过流式定量调节性T细胞(Tregs)和TIGIT+Tregs的比例。在体外实验中,将ad-IL-10转染到巨噬细胞中，然后检测细胞凋亡，吞噬作用,和CD163、CD16/32和CD206表达。检测并验证IL-10、miR-155和SOCS5的表达及相互关系。进行拯救实验以通过组合处理ad-IL-10和miR-155的过表达来评估巨噬细胞功能。结果：在小鼠心脏移植过程中，观察到慢性排斥反应中IL-10的表达显着降低。Ad-IL-10处理的小鼠表现出减少的病理损伤，血管周围纤维化，凋亡，炎症,和iNOS+和CD16/32+表达，增加Treg/TIGIT+Treg细胞，Arg-1+和CD206+细胞比例。Ad-IL-10处理的巨噬细胞在体外显示凋亡减少，改善吞噬作用，和M2极化。机械上,IL-10负调控miR-155激活SOCS5。miR-155的过表达可逆转IL-10介导的巨噬细胞功能的正调节。结论:IL-10下调miR-155并激活SOCS5,从而促进巨噬细胞M2极化,减轻心脏移植后慢性排斥反应。
