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Inflammasome-mediated Caspase-1 Activation Regulates the Secretion of IL-1 beta & IL-18
Nod-like receptors (NLRs) are a subset of pattern recognition receptors (PRRs) found in the cytosol that are essential for detecting invading pathogens and initiating the innate immune response. NLRs are activated either by a variety of bacterial, fungal, and viral molecules that contain pathogen-associated molecular patterns (PAMPs), or by nonmicrobial danger signals (DAMPs) released from damaged cells. Upon activation, some NLRs oligomerize to form multiprotein inflammasome complexes that serve as platforms for the recruitment, cleavage, and activation of inflammatory caspases. Inflammasome oligomerization required two signals, a priming signal that results in the NFkB- and AP-1-dependent transcription of Pro-IL-1 beta and Pro-IL-18, and a second signal that promotes indirect activation of the inflammasome, such as ion or membrane perturbations, reactive oxygen species (ROS), or ATP. Inflammasome oligomerization leads to Caspase-1 activation, followed by the maturation and secretion of IL-1 beta and IL-18, and in some cases, an inflammatory form of cell death known as pyroptosis. Similar to Toll-like receptor (TLR) signaling, both IL-1 beta and IL-18 activate the NFkB, JNK, and p38 MAPK signaling pathways to induce the expression of pro-inflammatory proteins and secondary mediators that promote the recruitment of immune cells to the site of infection. In addition, IL-18 enhances the cytolytic activity of natural killer (NK) cells and promotes IFN-gamma production. Four inflammasome complexes (NLRP1, NLRP3, IPAF, and AIM2) have been partially characterized to date. These complexes contain a specific NLR family protein or AIM2, the ASC and/or Cardinal adaptor proteins, and Pro-Caspase-1. Although the secretion of IL-1 beta and IL-18 are intended to combat infection, constitutive inflammasome activation and the subsequent over-production of IL-1 beta or IL-18 can have detrimental effects that are associated with autoinflammatory and autoimmune disorders. For these reasons, mechanisms that inhibit IL-1 beta and IL-18 signaling are of interest. Decoy or soluble receptors that sequester IL-1 beta, non-signaling IL-1 beta antagonists, and disruption of IL-1 receptor heterodimerization are intrinsic pathways that inhibit IL-1 beta signaling. Similarly, naturally occuring IL-18 binding protein (IL-18 BP) can prevent IL-18 from binding to its receptor. Further research is necessary to characterize how inflammasome complexes are activated, the mechanisms by which IL-1 beta and IL-18 singaling can be regulated, and both the beneficial and detrimental effects associated with the inflammasome pathway. These findings may have therapeutic implications for inflammasome-related disorders, including autoinflammatory disorders, Crohn's disease, type II diabetes, gout, vitiligo, asbestosis, and Alzheimer's disease.