IL-17A-mediated mitochondrial dysfunction induces pyroptosis in colorectal cancer cells and promotes CD8 + T-cell tumour infiltration
Abstract Background Interleukin-17A (IL-17A), a proinflammatory cytokine primarily secreted by Th17 cells, γδT cells and natural killer T (NKT) cells, performs essential roles in the microenvironment of certain inflammation-related tumours by regulating cancer growth and tumour elimination proved in...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-05-01
|
| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-023-04187-3 |
| _version_ | 1797822697317597184 |
|---|---|
| author | Wen-Qing Feng Yu-Chen Zhang Zhuo-Qing Xu Su-Yue Yu Jian-ting Huo Abudumaimaitijiang Tuersun Min-Hua Zheng Jing-Kun Zhao Ya-Ping Zong Ai-Guo Lu |
| author_facet | Wen-Qing Feng Yu-Chen Zhang Zhuo-Qing Xu Su-Yue Yu Jian-ting Huo Abudumaimaitijiang Tuersun Min-Hua Zheng Jing-Kun Zhao Ya-Ping Zong Ai-Guo Lu |
| author_sort | Wen-Qing Feng |
| collection | DOAJ |
| description | Abstract Background Interleukin-17A (IL-17A), a proinflammatory cytokine primarily secreted by Th17 cells, γδT cells and natural killer T (NKT) cells, performs essential roles in the microenvironment of certain inflammation-related tumours by regulating cancer growth and tumour elimination proved in previous literature. In this study, the mechanism of IL-17A that induces mitochondrial dysfunction promoted pyroptosis has been explored in colorectal cancer cells. Method The records of 78 patients diagnosed with CRC were reviewed via the public database to evaluate clinicopathological parameters and prognosis associations of IL-17A expression. The colorectal cancer cells were treated with IL-17A, and the morphological characteristics of those cells were indicated by scanning electron microscope and transmission electron microscope. After IL-17A treatment, mitochondrial dysfunction was tested by mitochondrial membrane potential (MMP) and reactive oxygen species (ROS). The expression of pyroptosis associated proteins including cleaved caspase-4, cleaved gasdermin-D (GSDMD), IL-1β, receptor activator of nuclear NOD-like receptor family pyrin domain containing 3 (NLRP3), apoptosis-associated speck like protein containing a card (ASC), and factor-kappa B was measured through western blotting. Results Positive IL-17A protein expression was observed in CRC compared to the non-tumour tissue. IL-17A expression indicates a better differentiation, earlier stage, and better overall survival in CRC. IL-17A treatment could induce mitochondrial dysfunction and stimulate intracellular reactive oxygen species (ROS) production. Furthermore, IL-17A could promote pyroptosis of colorectal cancer cells and significantly increase the secretion of inflammatory factors. Nevertheless, the pyroptosis induced by IL-17A could be inhibited through the pre-treatment with Mito-TEMPO (a mitochondria-targeted superoxide dismutase mimetic with superoxide and alkyl radical scavenging properties) or Z-LEVD-FMK (caspase-4 inhibitor, fluoromethylketone). Additionally, after being treated with IL-17A, an increasing number of CD8 + T cells showed in mouse-derived allograft colon cancer models. Conclusion IL-17A, as a cytokine mainly secreted by γδT cells in the colorectal tumour immune microenvironment, can regulate the tumour microenvironment in multiple ways. IL-17A could induce mitochondrial dysfunction and pyroptosis through the ROS/NLRP3/caspase-4/GSDMD pathway, and promote intracellular ROS accumulation. In addition, IL-17A can promote the secretion of inflammatory factors such as IL-1β、IL-18 and immune antigens, and recruit CD8 + T cells to infiltrate tumours. Graphical Abstract |
| first_indexed | 2024-03-13T10:12:57Z |
| format | Article |
| id | doaj.art-cb51319b20d04e3ea9781aaa21ee1e4b |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-03-13T10:12:57Z |
| publishDate | 2023-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-cb51319b20d04e3ea9781aaa21ee1e4b2023-05-21T11:25:41ZengBMCJournal of Translational Medicine1479-58762023-05-0121111710.1186/s12967-023-04187-3IL-17A-mediated mitochondrial dysfunction induces pyroptosis in colorectal cancer cells and promotes CD8 + T-cell tumour infiltrationWen-Qing Feng0Yu-Chen Zhang1Zhuo-Qing Xu2Su-Yue Yu3Jian-ting Huo4Abudumaimaitijiang Tuersun5Min-Hua Zheng6Jing-Kun Zhao7Ya-Ping Zong8Ai-Guo Lu9Department of General Surgery, Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of General Surgery, Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of General Surgery, Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of General Surgery, Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of General Surgery, Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of General Surgery, Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of General Surgery, Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of General Surgery, Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of General Surgery, Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of General Surgery, Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineAbstract Background Interleukin-17A (IL-17A), a proinflammatory cytokine primarily secreted by Th17 cells, γδT cells and natural killer T (NKT) cells, performs essential roles in the microenvironment of certain inflammation-related tumours by regulating cancer growth and tumour elimination proved in previous literature. In this study, the mechanism of IL-17A that induces mitochondrial dysfunction promoted pyroptosis has been explored in colorectal cancer cells. Method The records of 78 patients diagnosed with CRC were reviewed via the public database to evaluate clinicopathological parameters and prognosis associations of IL-17A expression. The colorectal cancer cells were treated with IL-17A, and the morphological characteristics of those cells were indicated by scanning electron microscope and transmission electron microscope. After IL-17A treatment, mitochondrial dysfunction was tested by mitochondrial membrane potential (MMP) and reactive oxygen species (ROS). The expression of pyroptosis associated proteins including cleaved caspase-4, cleaved gasdermin-D (GSDMD), IL-1β, receptor activator of nuclear NOD-like receptor family pyrin domain containing 3 (NLRP3), apoptosis-associated speck like protein containing a card (ASC), and factor-kappa B was measured through western blotting. Results Positive IL-17A protein expression was observed in CRC compared to the non-tumour tissue. IL-17A expression indicates a better differentiation, earlier stage, and better overall survival in CRC. IL-17A treatment could induce mitochondrial dysfunction and stimulate intracellular reactive oxygen species (ROS) production. Furthermore, IL-17A could promote pyroptosis of colorectal cancer cells and significantly increase the secretion of inflammatory factors. Nevertheless, the pyroptosis induced by IL-17A could be inhibited through the pre-treatment with Mito-TEMPO (a mitochondria-targeted superoxide dismutase mimetic with superoxide and alkyl radical scavenging properties) or Z-LEVD-FMK (caspase-4 inhibitor, fluoromethylketone). Additionally, after being treated with IL-17A, an increasing number of CD8 + T cells showed in mouse-derived allograft colon cancer models. Conclusion IL-17A, as a cytokine mainly secreted by γδT cells in the colorectal tumour immune microenvironment, can regulate the tumour microenvironment in multiple ways. IL-17A could induce mitochondrial dysfunction and pyroptosis through the ROS/NLRP3/caspase-4/GSDMD pathway, and promote intracellular ROS accumulation. In addition, IL-17A can promote the secretion of inflammatory factors such as IL-1β、IL-18 and immune antigens, and recruit CD8 + T cells to infiltrate tumours. Graphical Abstracthttps://doi.org/10.1186/s12967-023-04187-3IL-17AColorectal cancerMitochondrial dysfunctionPyroptosisCD8 + T |
| spellingShingle | Wen-Qing Feng Yu-Chen Zhang Zhuo-Qing Xu Su-Yue Yu Jian-ting Huo Abudumaimaitijiang Tuersun Min-Hua Zheng Jing-Kun Zhao Ya-Ping Zong Ai-Guo Lu IL-17A-mediated mitochondrial dysfunction induces pyroptosis in colorectal cancer cells and promotes CD8 + T-cell tumour infiltration Journal of Translational Medicine IL-17A Colorectal cancer Mitochondrial dysfunction Pyroptosis CD8 + T |
| title | IL-17A-mediated mitochondrial dysfunction induces pyroptosis in colorectal cancer cells and promotes CD8 + T-cell tumour infiltration |
| title_full | IL-17A-mediated mitochondrial dysfunction induces pyroptosis in colorectal cancer cells and promotes CD8 + T-cell tumour infiltration |
| title_fullStr | IL-17A-mediated mitochondrial dysfunction induces pyroptosis in colorectal cancer cells and promotes CD8 + T-cell tumour infiltration |
| title_full_unstemmed | IL-17A-mediated mitochondrial dysfunction induces pyroptosis in colorectal cancer cells and promotes CD8 + T-cell tumour infiltration |
| title_short | IL-17A-mediated mitochondrial dysfunction induces pyroptosis in colorectal cancer cells and promotes CD8 + T-cell tumour infiltration |
| title_sort | il 17a mediated mitochondrial dysfunction induces pyroptosis in colorectal cancer cells and promotes cd8 t cell tumour infiltration |
| topic | IL-17A Colorectal cancer Mitochondrial dysfunction Pyroptosis CD8 + T |
| url | https://doi.org/10.1186/s12967-023-04187-3 |
| work_keys_str_mv | AT wenqingfeng il17amediatedmitochondrialdysfunctioninducespyroptosisincolorectalcancercellsandpromotescd8tcelltumourinfiltration AT yuchenzhang il17amediatedmitochondrialdysfunctioninducespyroptosisincolorectalcancercellsandpromotescd8tcelltumourinfiltration AT zhuoqingxu il17amediatedmitochondrialdysfunctioninducespyroptosisincolorectalcancercellsandpromotescd8tcelltumourinfiltration AT suyueyu il17amediatedmitochondrialdysfunctioninducespyroptosisincolorectalcancercellsandpromotescd8tcelltumourinfiltration AT jiantinghuo il17amediatedmitochondrialdysfunctioninducespyroptosisincolorectalcancercellsandpromotescd8tcelltumourinfiltration AT abudumaimaitijiangtuersun il17amediatedmitochondrialdysfunctioninducespyroptosisincolorectalcancercellsandpromotescd8tcelltumourinfiltration AT minhuazheng il17amediatedmitochondrialdysfunctioninducespyroptosisincolorectalcancercellsandpromotescd8tcelltumourinfiltration AT jingkunzhao il17amediatedmitochondrialdysfunctioninducespyroptosisincolorectalcancercellsandpromotescd8tcelltumourinfiltration AT yapingzong il17amediatedmitochondrialdysfunctioninducespyroptosisincolorectalcancercellsandpromotescd8tcelltumourinfiltration AT aiguolu il17amediatedmitochondrialdysfunctioninducespyroptosisincolorectalcancercellsandpromotescd8tcelltumourinfiltration |