Basophils Trigger Fibroblast Activation in Cardiac Allograft Fibrosis Development
Basophils Trigger Fibroblast Activation in Cardiac Allograft Fibrosis Development
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DOI：
10.1111/ajt.13764
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发表时间：
2016-09-01
影响因子：
8.8
通讯作者：
Mack, M.
中科院分区：
文献类型：
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作者：
Schiechl, G.;Hermann, F. J.;Mack, M.
纤维化是心脏移植物慢性排斥反应的主要组成部分。虽然几种细胞类型能够产生胶原蛋白，但常驻（供体来源的）成纤维细胞主要负责细胞外基质蛋白的过量产生。目前尚不清楚哪些细胞调节同种异体移植物纤维化中结缔组织成分的产生，以及嗜碱性粒细胞作为促纤维化细胞因子的潜在产生者如何参与这一过程。我们在一个完全MHC不匹配的心脏移植模型中研究了这个问题，该模型通过短暂的CD 4（+）T细胞耗竭来防止急性排斥反应。该模型的特征在于白细胞的心肌浸润和间质纤维化和同种异体移植物血管病变的发展。使用嗜碱性粒细胞，IL-4缺乏受体和IL-4受体缺乏移植物的耗竭，我们表明嗜碱性粒细胞和IL-4在成纤维细胞的活化和纤维化器官重塑的发展中起着至关重要的作用。在缺乏CD 4（+）T细胞的情况下，嗜碱性粒细胞是移植物中IL-4的主要来源，并有助于肌成纤维细胞的扩增、胶原的间质沉积和同种异体移植物血管病变的发展。我们的研究结果表明，嗜碱性粒细胞触发肌成纤维细胞产生各种结缔组织元素。Schiechl埃塔尔在心脏移植慢性排斥模型中发现，移植物浸润的嗜碱性粒细胞以白细胞介素4依赖的方式参与移植物血管病变和纤维化的发生。
Fibrosis is a major component of chronic cardiac allograft rejection. Although several cell types are able to produce collagen, resident (donor-derived) fibroblasts are mainly responsible for excessive production of extracellular matrix proteins. It is currently unclear which cells regulate production of connective tissue elements in allograft fibrosis and how basophils, as potential producers of profibrotic cytokines, are involved this process. We studied this question in a fully MHC-mismatched model of heart transplantation with transient depletion of CD4(+) T cells to largely prevent acute rejection. The model is characterized by myocardial infiltration of leukocytes and development of interstitial fibrosis and allograft vasculopathy. Using depletion of basophils, IL-4-deficient recipients and IL-4 receptor-deficient grafts, we showed that basophils and IL-4 play crucial roles in activation of fibroblasts and development of fibrotic organ remodeling. In the absence of CD4(+) T cells, basophils are the predominant source of IL-4 in the graft and contribute to expansion of myofibroblasts, interstitial deposition of collagen and development of allograft vasculopathy. Our results indicated that basophils trigger the production of various connective tissue elements by myofibroblasts. Basophil-derived IL-4 may be an attractive target for treatment of chronic allograft rejection.In a model of chronic cardiac allograft rejection, Schiechl etal show that graft-infiltrating basophils contribute to the development of allograft vasculopathy and fibrosis in an interleukin-4-dependent manner.