The P2X7 Receptor Promotes Colorectal Inflammation and Tumorigenesis by Modulating Gut Microbiota and the Inflammasome

Abstract

Background: Given the role of the P2X7 receptor (P2X7R) in inflammatory bowel diseases (IBD), we investigated its role in the development and progression of colitis-associated colorectal cancer (CA-CRC). Methods: CA-CRC was induced in P2X7R+/+ and P2X7R−/− mice with azoxymethane (AOM) combined with dextran sodium sulfate (DSS). In a therapeutic protocol, P2X7R+/+ mice were treated with a P2X7R-selective inhibitor (A740003). Mice were evaluated with follow-up video endoscopy with endoluminal ultrasound biomicroscopy. Colon tissue was analyzed for histological changes, densities of immune cells, expression of transcription factors, cytokines, genes, DNA methylation, and microbiome composition of fecal samples by sequencing for 16S rRNA. Results: The P2X7R+/+ mice displayed more ulcers, tumors, and greater wall thickness, than the P2X7R−/− and the P2X7R+/+ mice treated with A740003. The P2X7R+/+ mice showed increased accumulation of immune cells, production of proinflammatory cytokines, activation of intracellular signaling pathways, and upregulation of NLRP3 and NLRP12 genes, stabilized after the P2X7R-blockade. Microbial changes were observed in the P2X7R−/− and P2X7R+/+-induced mice, partially reversed by the A740003 treatment. Conclusions: Regulatory mechanisms activated downstream of the P2X7R in combination with signals from a dysbiotic microbiota result in the activation of intracellular signaling pathways and the inflammasome, amplifying the inflammatory response and promoting CA-CRC development.

Innate lymphoid cells in early tumor development

“…The role of extracellular ATP and adenosine in tumor development has not been extensively studied and related studies have provided contradictory results. For example, studies assessing the role of the ATP receptor P2X7R in inflammationassociated CRC models have described an increase as well a reduction of tumor incidence in mice deficient for P2X7R (86,87). Evidence for the involvement of ATP and adenosine in activating ILC responses was provided in the context of tissue repair and inflammation.…”

Gut-immunity-joint axis: a new therapeutic target for gouty arthritis

“…In a therapeutic study, P2X7R +/+ mice were treated with the P2X7R selective inhibitor A740003.Video endoscopy and endoluminal ultrasound biomicroscopy revealed histological changes in colonic tissue.Analyses showed increased accumulation of immune cells, increased proinflammatory cytokine production and upregulated NLRP3 and NLRP12 genes in P2X7R +/+ mice, which were alleviated by P2X7R inhibition. Microbial alterations in P2X7R −/− and P2X7R+/+-induced mice were partially reversed by A740003, suggesting that the interaction between P2X7R and dysbiotic microbiota signals triggers intracellular pathways, inflammasome activation and exacerbates inflammation (Bernardazzi et al, 2022) (Figure 2C). In a murine model of alcoholic liver disease (ALD), carnosic acid (CA) mitigates ethanol-triggered lipid accumulation in AML12 cells and diminishes IL-1β release by suppressing the P2X7R-NLRP3 pathway in murine peritoneal macrophages (MPM) (Zuo et al, 2023).…”

The role of the purinergic ligand-gated ion channel 7 receptor in common digestive system cancers

“…In addition, AOM/DSS treated P2X7R +/+ mice induce upregulation of the NLRP3, NLRP12, MAPK1 and IL-1β target gene in mouse model. In protein level, it enhances the expression of NF-κB and phosphorylated ERK (Bernardazzi et al, 2022). Adinolfi et al showed that the expression of P2X7R promoted the growth of colon cancer in vivo.…”