Transplantation · 2020
Nlrp3 Inflammasome Inhibitor MCC950 Ameliorates Obliterative Bronchiolitis by Inhibiting Th1/Th17 Response and Promoting Treg Response After Orthotopic Tracheal Transplantation in Mice.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Xu Kai-Ying, Tong Song, Wu Chuang-Yan, Ding Xiang-Chao, Chen Jiu-Ling, Ming Yu, Wang Si-Hua
Аннотация
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.
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.