Zhang Zhiyong, Chen Ying, Yin Yuxin, Chen Yuxi, Chen Qianyu, Bing Ziqian, Zheng Yaojun, Hou Yayi, Shen Sunan, Chen Yitian, Wang Tingting
The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, China.
Department of Medical Oncology, School of Medicine, Jingling Hospital, Nanjing University, Nanjing, China.
Int Immunopharmacol. 2022 Dec;113(Pt B):109430. doi: 10.1016/j.intimp.2022.109430. Epub 2022 Nov 13.
Our previous studies showed that Candida tropicalis promoted colorectal cancer (CRC) by activating the function of MDSCs. However, underlying molecular mechanisms remains to be further investigated. In the present study, we indicated that C. tropicalis induced NLRP3 inflammasome activation through Dectin-3 in myeloid-derived suppressor cells (MDSCs). Mechanistically, we identified that C. tropicalis significantly enhanced the levels of glycolysis dependent on glycogen metabolism in MDSCs, which was required for NLRP3 inflammasome activation. C. tropicalis-induced NLRP3 inflammasome activation of MDSCs required the first priming signal and the second activation signal. For one thing, C. tropicalis promoted transcription of Nlrp3, Pro-caspase-1 and IL-1β genes through activation of JAK-STAT1 signaling pathway. For another, mtROS as the second activation signal mediated C. tropicalis-induced activation of NLRP3 inflammasome. Pharmacological inhibition of NLRP3 inflammasome activation abolished the pro-tumorigenic effect of C. tropicalis in an AOM/DSS-induced CAC mice model and significantly reduced C. tropicalis-promoted infiltration of MDSCs in colon tumors. Finally, in human CRC samples, the expression of STAT1, p-STAT1 and NLRP3 was elevated in MDSCs infiltrated by CRC. Collectively, these findings shed light on a previously unidentified mechanism by which C. tropicalis induces NLRP3 inflammasome activation in MDSCs to contribute to the progression of CRC. And STAT1-NLRP3 axis might represent a prospective therapeutic target for the treatment of CRC.
我们之前的研究表明，热带念珠菌通过激活髓源性抑制细胞（MDSCs）的功能促进结直肠癌（CRC）。然而，潜在的分子机制仍有待进一步研究。在本研究中，我们指出热带念珠菌通过髓源性抑制细胞中的Dectin-3诱导NLRP3炎性小体激活。机制上，我们发现热带念珠菌显著提高了髓源性抑制细胞中依赖糖原代谢的糖酵解水平，这是NLRP3炎性小体激活所必需的。热带念珠菌诱导的髓源性抑制细胞NLRP3炎性小体激活需要第一个启动信号和第二个激活信号。一方面，热带念珠菌通过激活JAK-STAT1信号通路促进Nlrp3、Pro-caspase-1和IL-1β基因的转录。另一方面，线粒体活性氧（mtROS）作为第二个激活信号介导热带念珠菌诱导的NLRP3炎性小体激活。药理学抑制NLRP3炎性小体激活消除了热带念珠菌在AOM/DSS诱导的结肠炎相关结直肠癌（CAC）小鼠模型中的促肿瘤作用，并显著减少了热带念珠菌促进的髓源性抑制细胞在结肠肿瘤中的浸润。最后，在人类结直肠癌样本中，在被结直肠癌浸润的髓源性抑制细胞中，STAT-1、p-STAT1和NLRP3的表达升高。总的来说，这些发现揭示了一种以前未被识别的机制，通过该机制热带念珠菌在髓源性抑制细胞中诱导NLRP3炎性小体激活，从而促进结直肠癌的进展。并且STAT1-NLRP3轴可能代表了结直肠癌治疗的一个潜在治疗靶点。
