Department of Internal Medicine, Ghent University, Ghent, B-9052, Belgium.
VIB-UGent Center for Inflammation Research, VIB, Ghent, B-9052, Belgium.
Nat Commun. 2018 Nov 19;9(1):4846. doi: 10.1038/s41467-018-07386-5.
Clostridium difficile is the leading cause of pseudomembranous colitis in hospitalized patients. C. difficile enterotoxins TcdA and TcdB promote this inflammatory condition via a cytotoxic response on intestinal epithelial cells (IECs), but the underlying mechanisms are incompletely understood. Additionally, TcdA and TcdB engage the Pyrin inflammasome in macrophages, but whether Pyrin modulates CDI pathophysiology is unknown. Here we show that the Pyrin inflammasome is not functional in IECs and that Pyrin signaling is dispensable for CDI-associated IEC death and for in vivo pathogenesis. Instead, our studies establish that C. difficile enterotoxins induce activation of executioner caspases 3/7 via the intrinsic apoptosis pathway, and demonstrate that caspase-3/7-mediated IEC apoptosis is critical for in vivo host defense during early stages of CDI. In conclusion, our findings dismiss a critical role for inflammasomes in CDI pathogenesis, and identify IEC apoptosis as a host defense mechanism that restricts C. difficile infection in vivo.
艰难梭菌是住院患者假膜性结肠炎的主要病因。艰难梭菌肠毒素 TcdA 和 TcdB 通过对肠上皮细胞（IECs）的细胞毒性反应促进这种炎症状态，但潜在的机制尚不完全清楚。此外，TcdA 和 TcdB 与巨噬细胞中的 Pyrin 炎性小体结合，但 Pyrin 是否调节 CDI 发病机制尚不清楚。在这里，我们表明 Pyrin 炎性小体在 IEC 中不起作用，并且 Pyrin 信号对于 CDI 相关的 IEC 死亡和体内发病机制是可有可无的。相反，我们的研究表明艰难梭菌肠毒素通过内在凋亡途径诱导执行器半胱天冬酶 3/7 的激活，并证明 caspase-3/7 介导的 IEC 凋亡对于 CDI 早期体内宿主防御至关重要。总之，我们的发现否定了炎性小体在 CDI 发病机制中的关键作用，并确定 IEC 凋亡是一种宿主防御机制，可限制体内艰难梭菌感染。
