Article

The Inflammasomes: Guardians of the Body

Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Annual Review of Immunology (Impact Factor: 39.33). 02/2009; 27(1):229-65. DOI: 10.1146/annurev.immunol.021908.132715
Source: PubMed

ABSTRACT

The innate immune system relies on its capacity to rapidly detect invading pathogenic microbes as foreign and to eliminate them. The discovery of Toll-like receptors (TLRs) provided a class of membrane receptors that sense extracellular microbes and trigger antipathogen signaling cascades. More recently, intracellular microbial sensors have been identified, including NOD-like receptors (NLRs). Some of the NLRs also sense nonmicrobial danger signals and form large cytoplasmic complexes called inflammasomes that link the sensing of microbial products and metabolic stress to the proteolytic activation of the proinflammatory cytokines IL-1beta and IL-18. The NALP3 inflammasome has been associated with several autoinflammatory conditions including gout. Likewise, the NALP3 inflammasome is a crucial element in the adjuvant effect of aluminum and can direct a humoral adaptive immune response. In this review, we discuss the role of NLRs, and in particular the inflammasomes, in the recognition of microbial and danger components and the role they play in health and disease.

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    • "IL-1b is transcribed as a larger pro-hormone, pro-IL-1b, and pro-IL-1b must be cleaved by caspase-1 to form the biologically active, mature form of IL-1b. The process of cleaving pro-IL-1b typically requires the formation and activation of an inflammasome, most often the nucleotidebinding domain and leucine-rich repeat containing family, pyrin domain containing 3 (NLRP3) inflammasome, an intracellular multiprotein complex that mediates processing and maturation of IL-1b via activation of caspase-1 (Martinon et al., 2009). Importantly , signaling at TLR4 initiates an intracellular signaling cascade to activate the immune-related transcription factor NF-kB (Kawai and Akira, 2010), which is a critical step in the formation of the NLRP3 inflammasome. "
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    • "It has been a consensus in the scientific literature that several identified NLRP3 activators also increase reactive oxygen species (ROS). It is well documented that activation of P2X7 is accompanied by production of intracellular ROS [13] [14] [15] [16] [17] [18]. Initial studies using inhibitors supported a model in which ROS are generated by NADPH oxidases during NLRP3-inflammasome activation [19]. "
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    • "Inflammasomes are typically composed of an immune sensor protein (a NOD-like receptor (NLR) such as NLRP1, NLRP3, NLRC4 or NLRP6), caspase-1, and, in many cases, the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD domain) [34]. Some inflammasomes are activated by direct interaction with specific pathogen-associated molecular patterns (PAMPs). "

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