Graft IL-33 regulates infiltrating macrophages to protect against chronic rejection
Graft IL-33 regulates infiltrating macrophages to protect against chronic rejection
复制标题
移植物 IL-33 调节浸润巨噬细胞以防止慢性排斥
DOI：
10.1172/jci133008
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发表时间：
2020-10-01
影响因子：
15.9
通讯作者：
Turnquist, Heoverlineth R.
中科院分区：
文献类型：
--
作者：
Li, Tengfang;Zhang, Zhongqiang;Turnquist, Heoverlineth R.
警报素是一种包含损伤相关分子模式的隔离自身分子，在组织损伤期间释放，以驱动先天免疫细胞促炎症反应。控制早期免疫反应的内源性负调节因子是否也在损伤部位释放尚不清楚。在此，我们确定基质细胞来源的警报蛋白白细胞介素 33 (IL-33) 是移植后早期直接限制移植物浸润巨噬细胞促炎能力的局部因素。通过评估心脏移植受者样本并使用小鼠心脏移植模型，我们确定同种异体移植物中 IL-33 上调以限制慢性排斥反应。缺乏 IL-33 的小鼠心脏移植显示出显着加速的血管闭塞和随后的纤维化，这并不是由于全身免疫反应改变所致。相反，移植物 IL-33 的缺乏会导致促炎 iNOS 巨噬细胞局部增加，从而加速移植物损失。 IL-33 促进巨噬细胞中与修复和调节功能相关的代谢程序，IL-33 的局部递送可防止 IL-33 缺陷的心脏移植物的慢性排斥。因此，我们认为 IL-33 代表了移植中的一种新型调节警报素，它通过抑制促炎巨噬细胞的局部激活来限制慢性排斥反应。在基于细胞外基质的材料中局部递送 IL-33 可能是用于预防慢性排斥反应的有前途的生物制剂。
Alarmins, sequestered self-molecules containing damage-associated molecular patterns, are released during tissue injury to drive innate immune cell proinflammatory responses. Whether endogenous negative regulators controlling early immune responses are also released at the site of injury is poorly understood, Herein, we establish that the stromal cell-derived alarmin interleukin 33 (IL-33) is a local factor that directly restricts the proinflammatory capacity of graft-infiltrating macrophages early after transplantation. By assessing heart transplant recipient samples and using a mouse heart transplant model, we establish that IL-33 is upregulated in allografts to limit chronic rejection. Mouse cardiac transplants lacking IL-33 displayed dramatically accelerated vascular occlusion and subsequent fibrosis, which was not due to altered systemic immune responses. Instead, a lack of graft IL-33 caused local augmentation of proinflammatory iNOS' macrophages that accelerated graft loss. IL-33 facilitated a metabolic program in macrophages associated with reparative and regulatory functions, and local delivery of IL-33 prevented the chronic rejection of IL-33-deficient cardiac transplants. Therefore, IL-33 represents what we believe is a novel regulatory alarmin in transplantation that limits chronic rejection by restraining the local activation of proinflammatory macrophages. The local delivery of IL-33 in extracellular matrix-based materials may be a promising biologic for chronic rejection prophylaxis.