Investigating the role of inflammatory caspases during disease-associated inflammation

Abstract

Caspases are a group of proteolytic enzymes involved in the co-ordination of cellular processes such as inflammation and apoptosis. Functional mechanisms surrounding the activation and signalling pathways mediated by inflammatory caspases (such as caspase-1, -4 and -5) are being intensively researched at present. It is well established that canonical inflammasome mediated caspase-1 activation promotes the maturation and secretion of pro-inflammatory cytokines such as IL-1β and IL-18, which further amplifies the pro-inflammatory immune response. However, activation of the non-canonical inflammasome (mediated by human caspase-4 and -5 or their murine homolog, caspase-11), serves as an additional pathway for enhancing canonical inflammasome activation in response to Gram-negative bacterial infection. This highlights the crucial importance of these caspases during the host immune response and caspase-1 regulation. As canonical activation of inflammasome signalling is a critical modulator of immune system homeostasis, its dysregulation leads to the development of a multitude of inflammatory disorders and also inflammatory associated cancers. Altered activity of caspase-1 and the canonical inflammasome has been implicated in the development of intestinal inflammatory diseases such as inflammatory bowel disease (IBD) and colitis associated cancer (CAC). However, there is still little known regarding the role of murine caspase-11 and human caspase-4 and -5 during acute and chronic disease associated inflammation of the gastrointestinal tract (GI).