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 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

Longitudinal Changes in Mitochondrial DNA Copy Number and Telomere Length in Patients with Parkinson’s Disease

“…IL-17A is a proinflammatory cytokine that exerts pleiotropic functions activating other inflammatory cytokines. IL-17A is also an important bridge between inflammation and immunity, and it can induce mitochondrial dysfunction by stimulating intracellular ROS production, thereby promoting pyroptosis, as shown in a colorectal cancer study [69]. Elevated mtDNA-CN means mitochondrial dysfunction which leads to oxidative stress and increases the production of proinflammatory cytokines.…”

Inhibition of HDAC2 sensitises antitumour therapy by promoting NLRP3/GSDMD‐mediated pyroptosis in colorectal cancer

“… 30 In CRC, emerging drugs have been reported to upregulate NLRP3 expression and activate the NLRP3 inflammasome, leading to pyroptosis. 31 , 32 Although these drugs have the potential to induce pyroptosis, they are not specific and therefore still show potential for the development of more targeted pyroptosis‐inducing drugs. A recent study showed significant alterations in the expression of NLRP3 inflammasome component genes in 15 of the 24 cancer types.…”

The gasdermin family: emerging therapeutic targets in diseases

“…NLRP3/GSDMD-dependent pyroptosis pathway has been implicated in the progression of cancer, including non-small cell lung cancer (NSCLC), 397 , 398 triple-negative breast cancer (TNBC), 399 ovarian cancer, 400 and colorectal cancer. 401 , 402 GSDMD is observed in differentiated cells of gastric cancer (GC) and exhibits colony formation inhibitory activity, potentially inhibiting cell proliferation. 153 GSDMD is also implicated in the invasive and metastatic potential of colorectal cancer cells and is a negative regulator.…”