Gastroenterology report · 2025
Gasdermin E-mediated intestinal epithelial pyroptosis promotes chemically induced colitis in mice.
СтатьяНазвание 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.
Wu Yi-Zhong, Xie Yao, Chen Lin, Ning Lei, Hu Xiao-Qi, Xu Xiao-Ping
Аннотация
BACKGROUND: Gasdermin E (GSDME) is a newly identified pyroptosis executioner and is upregulated in the intestinal epithelial cell (IEC) of ulcerative colitis (UC) patients. However, the effects of epithelial GSDME on UC remain unknown.
METHODS: Bone marrow chimera experiments were performed to investigate the role of GSDME in nonhematopoietic cells, mainly including IECs. An FITC-dextran assay was used to assess the integrity of the intestinal epithelial barrier.
RESULTS: Gsdme-/- chimeras that were reconstituted with wild-type bone marrow cells exhibited lower weight loss, disease activity index, colon shortening, and histology scores than wild-type chimeras after treatment with dextran sulfate sodium (DSS). However, Gsdme +/+ chimeras that were reconstituted with Gsdme-deficient bone marrow cells were not protected from DSS-induced colitis compared with wild-type chimeras. Importantly, DSS treatment activated Caspase-3 and cleaved GSDME to generate GSDME-N terminal fragments that are responsible for the induction of pyroptosis in IECs, but not in the intestinal lamina propria cell. Additionally, GSDME deficiency inhibited DSS-induced disruption of the intestinal epithelial barrier. Mechanistically, GSDME-mediated IEC pyroptosis is dependent on Caspase-3 activation, which is supported by the observation that the Caspase-3 inhibitor Z-DEVD-FMK inhibited DSS-induced GSDME cleavage in IECs.
CONCLUSIONS: We show that GSDME-mediated epithelial pyroptosis contributes to the development of DSS-induced colitis by promoting intestinal inflammation and disrupting the intestinal epithelial barrier.
METHODS: Bone marrow chimera experiments were performed to investigate the role of GSDME in nonhematopoietic cells, mainly including IECs. An FITC-dextran assay was used to assess the integrity of the intestinal epithelial barrier.
RESULTS: Gsdme-/- chimeras that were reconstituted with wild-type bone marrow cells exhibited lower weight loss, disease activity index, colon shortening, and histology scores than wild-type chimeras after treatment with dextran sulfate sodium (DSS). However, Gsdme +/+ chimeras that were reconstituted with Gsdme-deficient bone marrow cells were not protected from DSS-induced colitis compared with wild-type chimeras. Importantly, DSS treatment activated Caspase-3 and cleaved GSDME to generate GSDME-N terminal fragments that are responsible for the induction of pyroptosis in IECs, but not in the intestinal lamina propria cell. Additionally, GSDME deficiency inhibited DSS-induced disruption of the intestinal epithelial barrier. Mechanistically, GSDME-mediated IEC pyroptosis is dependent on Caspase-3 activation, which is supported by the observation that the Caspase-3 inhibitor Z-DEVD-FMK inhibited DSS-induced GSDME cleavage in IECs.
CONCLUSIONS: We show that GSDME-mediated epithelial pyroptosis contributes to the development of DSS-induced colitis by promoting intestinal inflammation and disrupting the intestinal epithelial barrier.