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


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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Available from: Fabio Martinon
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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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    ABSTRACT: Stress and glucocorticoids (GCs) have universally been considered to be anti-inflammatory, however in recent years, stress and GCs have been found to exert permissive effects (immunological priming) on neuroinflammatory processes. This phenomenon of priming is characterized by prior stress or GC exposure potentiating the neuroinflammatory response to a subsequent immune challenge. A considerable body of evidence is discussed here that supports this permissive effect of stress and GCs.In light of this evidence, a mechanism of neuroinflammatory priming is proposed involving a signal cascade in the brain involving danger-associated molecular patterns (HMGB-1) and inflammasomes (NLRP3), which results in an exaggerated or amplified neuroinflammatory response and subsequently, the amplification of the physiological and behavioral sequelae of this response (i.e. sickness). Finally, we explore the notion that stressor-induced sensitization of the neuroimmune microenvironment may predispose individuals to psychiatric disorders, in which exaggerated innate immune/inflammatory responses in the brain are now thought to play a key role.
    Full-text · Article · Dec 2015
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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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    ABSTRACT: Crystalline cellulose nanocrystals (CNCs) have emerged as novel materials for a wide variety of important applications such as nanofillers, nanocomposites, surface coatings, regenerative medicine and potential drug delivery. CNCs have a needle-like structure with sizes in the range of 100-200. nm long and 5-20. nm wide and a mean aspect ratio 10-100. Despite the great potential applicability of CNCs, very little is known about their potential immunogenicity. Needle-like materials have been known to evoke an immune response in particular to activate the (NOD-. like receptor, pyrin domain-containing 3)-inflammasome/IL-1β (Interleukin 1β) pathway. In this study we evaluated the capacity of unmodified CNC and its cationic derivatives CNC-AEM (aminoethylmethacrylate)1, CNC-AEM2, CNC-AEMA(aminoethylmethacrylamide)1 and CNC-AEMA2 to stimulate NLRP3-inflammasome/IL-1β pathway and enhance the production of mitochondrial reactive oxygen species (ROS). Mouse macrophage cell line (J774A.1) was stimulated for 24. h with 50. μg/mL with unmodified CNC and its cationic derivatives. Alternatively, J774A1 or PBMCs (peripheral blood mononuclear cells) were stimulated with CNC-AEMA2 in presence or absence of LPS (lipopolysaccharide). IL-1β secretion was analyzed by ELISA, mitochondrial function by JC-1 staining and ATP content. Intracellular and mitochondrial reactive oxygen species (ROS) were assessed by DCF-DA (2',7'-dichlorodihydrofluorescein diacetate) and MitoSOX, respectively. Mitochondrial ROS and extracellular ATP were significantly increased in cells treated with CNC-AEMA2, which correlates with the strongest effects on IL-1β secretion in non-primed cells. CNC-AEMA2 also induced IL-1βsecretion in LPS-primed and non-primed PBMCs. Our data suggest that the increases in mitochondrial ROS and ATP release induced by CNC-AEMA2 may be associated with its capability to evoke immune response. We demonstrate the first evidence that newly synthesized cationic cellulose nanocrystal derivative, CNC-AEMA2, has immunogenic properties, which may lead to the development of a potential non-toxic and safe nanomaterial to be used as a novel adjuvant for vaccines.
    Full-text · Article · Dec 2015
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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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