Inflammasomes in Colitis and Colorectal Cancer: Mechanism of Action and Therapies

Abstract

Colorectal cancer is a multifactorial disease and a leading cause of cancer-related deaths worldwide. Inflammation is a driver across multiple stages in the development of colorectal cancer. The inflammasome is a cytosolic multiprotein complex of the innate immune system central to the regulation of inflammation, pyroptosis, and other cellular processes important for maintaining gut homeostasis. Studies using mouse models of colitis and colitis-associated colorectal cancer have highlighted diverse and sometimes contrasting roles of inflammasomes in maintaining a balance between intestinal barrier function and the gut microbiota. In addition, persistent and/or dysregulated stimulation of inflammasome sensors finetune inflammation and tumorigenesis in the intestine. This review highlights the emerging role of inflammasome signaling in colitis and colitis-associated colorectal cancer. We also review the key mechanisms by which inflammasome signaling modulate inflammation and tumor development. Finally, we speculate the importance of using more tightly regulated experimental approaches to examine the role of gut microbiota in colorectal cancer.

Keywords: Inflammasomes; cancer; colitis; innate immunity; microbiome; microbiota; organelle; therapy.

Figure 1

Critical role of inflammasomes and related molecules in colitis and colorectal cancer. The inflammasome sensors NLRP1b, NLRP3, NLRP6, and Pyrin can sense danger-associated molecular patterns (DAMPs) and/or pathogen-associated molecular patterns (PAMPs) leading to the formation of an inflammasome complex containing the adaptor protein ASC and the cysteine protease caspase-1. Activation of caspase-1 mediates the cleavage of pro-IL-1β, pro-IL-18, and the pore-forming protein gasdermin D (GSDMD) into their bioactive form. Human caspase-4, 5 or mouse caspase-11 can sense intracellular lipopolysaccharide (one of the PAMPs derived from Gram-negative bacteria) leading to cleavage of GSDMD and pyroptosis. The pore-forming fragment of gasdermin D (GSDMD-N) induces potassium efflux which activates the NLRP3 inflammasome and caspase-1-dependent maturation of IL-1β and IL-18. IL-1β is linked to the development of colitis and colorectal cancer, however, IL-1R signaling elicits cell-type-specific responses. For instance, IL-1R1 signaling in epithelial and T-cells is pro-tumorigenic, whereas in myeloid cells, particularly neutrophils, prevents inflammation and colorectal cancer progression. IL-18 and IL-18 receptor signaling confer protection against both colitis and colorectal cancer. IL-18 also promotes downregulation of soluble IL-22-binding protein (IL-22BP), which controls the ability of IL-22 to suppress inflammation or induce tumorigenesis in the gut. In addition, NLRP6 promotes the secretion of mucin and anti-microbial peptides (AMPs) in intestinal epithelial cells and provides protection against colitis and colitis-associated colorectal cancer. AIM2 inhibits the phosphorylation of DNA-dependent protein kinase (DNA-PK) which induces colorectal tumorigenesis via activation of AKT and the transcription factor MYC. NAIP1–6 proteins, present in mouse intestinal epithelial cells, can control tumorigenesis by limiting the phosphorylation of signal transducer and activator of transcription 3 (STAT3). Furthermore, NLRC4 can block cellular proliferation and protects against colorectal cancer. In addition to the protective roles, inflammasomes and their components have detrimental roles in colitis and colorectal cancer.