NLRP3 炎性体抑制剂 MCC950 通过抑制小鼠原位气管移植后 Th1/Th17 反应和促进 Treg 反应来改善闭塞性细支气管炎。
Nlrp3 Inflammasome Inhibitor MCC950 Ameliorates Obliterative Bronchiolitis by Inhibiting Th1/Th17 Response and Promoting Treg Response After Orthotopic Tracheal Transplantation in Mice.
机构信息
Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China.
出版信息
Transplantation. 2020 Jun;104(6):e151-e163. doi: 10.1097/TP.0000000000003208.
BACKGROUND
Obliterative bronchiolitis (OB) remains the major complication limiting long-term survival of patients after lung transplantation. We aimed to explore the effects of the selective NACHT, LRR, and PYD domains-containing protein 3 (Nlrp3) inflammasome inhibitor MCC950 on the pathogenesis of OB.
METHODS
Mouse orthotopic tracheal transplants were performed to mimic OB. MCC950 (50 mg/kg) or saline was intraperitoneally injected daily. The luminal occlusion rate and collagen deposition were evaluated by hematoxylin and eosin and Masson's trichrome staining, respectively. Infiltration of CD4+, CD8+ T cells, and neutrophils was detected with immunohistochemical staining. The frequencies of T helper 1 cell (Th1), T helper 17 cell (Th17), and regulatory T cells (Treg) were measured by flow cytometry. Cytokine levels were measured by ELISA kits.
RESULTS
MCC950 treatment significantly inhibited Nlrp3 inflammasome activation after allogeneic tracheal transplant and markedly decreased the luminal occlusion rate and collagen deposition in the allograft. The numbers of infiltrating CD4+, CD8+ T cells, and neutrophils in the allograft were also significantly reduced by MCC950 treatment. MCC950 dramatically decreased the frequencies of Th1/Th17 cells and the levels of interferon gamma/interleukin (IL)-17A and increased the Treg cell frequencies and IL-10 level; however, these effects were abolished by the addition of IL-1β and IL-18 both in vitro and in vivo. OB was also rescued by the addition of IL-1β and/or IL-18.
CONCLUSIONS
Blocking Nlrp3 inflammasome activation with MCC950 ameliorates OB lesions. The mechanistic analysis showed that MCC950 regulated the balance of Th1/Th17 and Treg cells and that this process is partially mediated by inhibition of IL-1β and IL-18. Therefore, targeting the Nlrp3 inflammasome is a promising strategy for controlling OB after lung transplantation.
背景
闭塞性细支气管炎（OB）仍然是肺移植后限制患者长期生存的主要并发症。我们旨在探讨选择性 NACHT、LRR 和 PYD 结构域包含蛋白 3（Nlrp3）炎症小体抑制剂 MCC950 对 OB 发病机制的影响。
方法
进行小鼠原位气管移植以模拟 OB。每天腹腔内注射 MCC950（50mg/kg）或生理盐水。通过苏木精和伊红以及 Masson 三色染色分别评估管腔闭塞率和胶原沉积。用免疫组织化学染色检测 CD4+、CD8+T 细胞和中性粒细胞的浸润。通过流式细胞术测量 T 辅助 1 细胞（Th1）、T 辅助 17 细胞（Th17）和调节性 T 细胞（Treg）的频率。通过 ELISA 试剂盒测量细胞因子水平。
结果
MCC950 治疗显著抑制同种异体气管移植后 Nlrp3 炎症小体的激活，并显著降低移植物的管腔闭塞率和胶原沉积。MCC950 治疗还显著减少了移植物中浸润的 CD4+、CD8+T 细胞和中性粒细胞的数量。MCC950 还显著降低了 Th1/Th17 细胞的频率和干扰素γ/白细胞介素（IL）-17A 的水平，并增加了 Treg 细胞的频率和 IL-10 水平；然而，这些作用在体内和体外均被添加 IL-1β 和 IL-18 所消除。体外和体内添加 IL-1β 和/或 IL-18 也可挽救 OB。
结论
用 MCC950 阻断 Nlrp3 炎症小体的激活可改善 OB 病变。机制分析表明，MCC950 调节了 Th1/Th17 和 Treg 细胞的平衡，这一过程部分通过抑制 IL-1β 和 IL-18 介导。因此，靶向 Nlrp3 炎症小体是控制肺移植后 OB 的一种有前途的策略。
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