Inflammasomes: Intracellular Regulators of Pathogen

Inflammasomes: Intracellular Regulators of Pathogen Recognition Host Defense & Inflammation
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Pattern recognition receptors (PRRs) expressed by macrophages, monocytes, dendritic cells, neutrophils, and epithelial cells play a critical role in activation of the innate immune response. Nod-like receptors (NLRs) are cytoplasmic PRRs that detect intracellular microbial components or endogenous danger signals. Following activation, some NLRs form inflammasome complexes that induce the cleavage and activation of Caspase-1, leading to the subsequent processing and secretion of IL-1 beta and IL-18. IL-1 beta and IL-18 induce the expression of secondary mediators that attract immune cells to the site of the infection. Although IL-1 beta and IL-18 have a beneficial role in promoting inflammation and eliminating infectious pathogens, mutations that result in constitutive inflammasome activation and the over­production of IL-1 beta and IL-18 have been linked to autoinflammatory and autoimmune disorders. Further research is necessary to identify factors that regulate inflammasome activation, to characterize the cell type-specific effects of NLR-/inflammasome-dependent signaling pathways, and to determine how defects in these signaling pathways contribute to the development and progression of inflammation-related pathological conditions.

 

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 bacterial, fungal, or 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 requires two signals, a priming signal that results in the 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 the activation of Caspase-1, 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. Inflammasome/Caspase-1-dependent secretion of IL-1 beta and IL-18 stimulates the inflammatory response by inducing the expression of secondary mediators that promote the recruitment of immune cells to the site of the infection. In addition, IL-18 enhances the cytolytic activity of natural killer (NK) cells and promotes IFN-gamma production. To date, four inflammasome complexes (NLRP1, NLRP3, IPAF, and AIM2) have been partially characterized. 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 overproduction 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 occurring 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 signaling 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, vitiligo, gout, asbestosis, and Alzheimer's disease.

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