The ‘speck’-tacular oversight of the NLRP3-pyroptosis pathway on gastrointestinal inflammatory diseases and tumorigenesis

Abstract

The NLRP3 inflammasome is an intracellular sensor and an essential component of the innate immune system involved in danger recognition. An important hallmark of inflammasome activation is the formation of a single supramolecular punctum, known as a speck, per cell, which is the site where the pro-inflammatory cytokines IL-1β and IL-18 are converted into their bioactive form. Speck also provides the platform for gasdermin D protein activation, whose N-terminus domain perforates the plasma membrane, allowing the release of mature cytokines alongside with a highly inflammatory form of cell death, namely pyroptosis. Although controlled NLRP3 inflammasome-pyroptosis pathway activation preserves mucosal immunity homeostasis and contributes to host defense, a prolonged trigger is deleterious and could lead, in genetically predisposed subjects, to the onset of inflammatory bowel disease, including Crohn's disease and ulcerative colitis, as well as to gastrointestinal cancer. Experimental evidence shows that the NLRP3 inflammasome has both protective and pathogenic abilities. In this review we highlight the impact of the NLRP3-pyroptosis axis on the pathophysiology of the gastrointestinal tract at molecular level, focusing on newly discovered features bearing pro- and anti-inflammatory and neoplastic activity, and on targeted therapies tested in preclinical and clinical trials.

The Role of Oxidative Stress in Tumorigenesis and Progression

“…In addition, ROS is involved in the activation of many immune cells, like CD8+ T cells [ 59 , 60 ], macrophages TG [ 61 ], and dendritic cells [ 62 ]. NLRP3 inflammasome is a crucial component of the innate immune system mediated by ROS [ 63 ] and contributes to various cancers like gastrointestinal tract [ 64 , 65 ] and breast cancer [ 66 ], while it is also demonstrated to be tumor-promoting in gastric and skin cancer [ 67 ]. The cGAS/STING pathway, which has been reported to be ROS mediated, exerts a crucial dichotomous function in the antitumor process, including agitating type I IFN induction in DCs, prompting antitumor CD8+ T cell responses, maintaining CD8+ T cell stemness, etc.…”