Novel Inflammasomes and Type II Diabetes, Intestinal Inflammation and Psoriasis as Newly Inflammasome-Related Diseases

Abstract

Inflammasomes are multiprotein complexes representing an activating platform for caspase-1. This enzyme processes the cytokines IL-1β, IL-18 and others into their bioactive variants leading to an inflammatory cascade. Mutations responsible for defects in inflammasome regulation cause severe autoinflammatory disorders.This review provides a short summary of new insights in the autoinflammatory field including the association of inflammasomes to diabetes, intestinal inflammation as well as psoriasis and communicates the ideas of two novel inflammasomes, recently discovered. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell 1: 133-144. 44. Goldbach-Mansky R, Kastner DL (2009) Autoinflammation: the prominent role of IL-1 in monogenic autoinflammatory diseases and implications for common illnesses. J Allergy Clin Immunol 6: 1141-1149. 45. Richards N, Schaner P, Diaz A, Stuckey J, Shelden E, et al. (2001) Interaction between pyrin and the apoptotic speck protein (ASC) modulates ASC-induced apoptosis. J Biol Chem 42: 39320-39329. 46. Chae JJ, Komarow HD, Cheng J, Wood G, Raben N, et al. (2003) Targeted disruption of pyrin, the FMF protein, causes heightened sensitivity to endotoxin and a defect in macrophage apoptosis. Mol Cell 3: 591-604.

Enzymatically Inactive Procaspase 1 stabilizes the ASC Pyroptosome and Supports Pyroptosome Spreading during Cell Division

“…Together with caspase-11 and -12 in mice and caspase-4, -5, and -12 in humans, caspase-1 belongs to the family of inflammatory caspases, which are produced as inactive forms. After the detection of pathogens or cytoplasmic danger signals, inactive caspase-1 monomers recruit to multiprotein complexes referred to as inflammasomes (1)(2)(3). In such inflammasomes, inactive procaspases are autoprocessed into caspase activation and recruitment domains (CARDs), 2 the p10 and the p20 subunits (4).…”

“…After the detection of pathogens or cytoplasmic danger signals, inactive caspase-1 monomers recruit to multiprotein complexes referred to as inflammasomes (1)(2)(3). In such inflammasomes, inactive procaspases are autoprocessed into caspase activation and recruitment domains (CARDs), 2 the p10 and the p20 subunits (4). Two p10 and two p20 proteins subsequently form the active caspase-1 tetramer, which then cleaves and thereby activates IL-1␤ in the so-called canonical inflammasome pathway (5,6).…”

Human Procaspase-1 Variants with Decreased Enzymatic Activity Are Associated with Febrile Episodes and May Contribute to Inflammation via RIP2 and NF-κB Signaling

“…Normally, inflammasome activation results in procaspase-1 autoprocessing to generate the active form. This heterotetrameric enzyme containing two p10 and two p20 subunits is able to process the proforms of IL-1b and IL-18 into their biologically active mature forms (1)(2)(3)(4)(5)(6)(7)(8). These cytokines subsequently participate in an appropriate response of the immune system to tissue damage or pathogen invasion (9) but also can play a role in autoinflammatory conditions (10).…”

Risk Factors in Hepatocellular Carcinoma

“…they make tissues more responsive to insulin and, therefore, decrease hyperinsulinemia [35]. If Hyperinsulinemia plays a role in increasing cancer risk and progression in diabetic patients, it is reasonable to expect that these drugs will have a different effect on association between diabetes and cancer [36,37].…”