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, Oct 04, 2015
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    • "These findings are consistent with a recent study that also found that stress increases expression of NLRP3 (Pan et al., 2014). Briefly, NLRP3 is an inflammasome component that mediates, in large part, processing and maturation of IL-1b (Martinon et al., 2009). Inflammasomes are multi-protein complexes that are involved in the activation of inflammatory caspases, which play a pivotal role in the processing and maturation of pro-inflammatory cytokines. "
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    ABSTRACT: High mobility group box-1 (HMGB1) is an endogenous danger signal or alarmin that mediates activation of the innate immune response including chemotaxis and pro-inflammatory cytokine release. HMGB1 has been implicated in the pathophysiology of several neuroinflammatory conditions including ischemia, traumatic brain injury, seizure and chronic ethanol use. In the present review, the unique structural and functional properties of HMGB1 will be explored including its affinity for multiple pattern recognition receptors (TLR2/TLR4), redox sensitivity and adjuvant-like properties. In light of recent evidence suggesting that HMGB1 may also mediate stress-induced sensitization of neuroinflammatory responses, mechanisms of HMGB1 action in neuroinflammatory priming are explored. A model of neuroinflammatory priming is developed wherein glucocorticoids induce synthesis and release of HMGB1 from microglia, which signals through TLR2/TLR4, thereby priming the NLRP3 inflammasome. We propose that if GCs reach a critical threshold as during a fight/flight response, they may thus function as an alarmin by inducing HMGB1, thereby preparing an organism's innate immune system (NLRP3 inflammasome priming) for subsequent immune challenges such as injury, trauma or infection, which are more likely to occur during a fight/flight response. In doing so, GCs may confer a significant survival advantage by enhancing the central innate immune and sickness response to immune challenges. Copyright © 2015. Published by Elsevier Inc.
    Brain Behavior and Immunity 03/2015; 48. DOI:10.1016/j.bbi.2015.03.010 · 5.89 Impact Factor
    • "The NLRP3 inflammasome protein complex facilitates production of active caspase-1 for generation of IL-1β and IL-18 from preforms (Netea et al., 2014). NLRP1, NLRP3, and NLRC4 are primary complexes (Martinon et al., 2009) governing caspase-1 activation for proteolytic processing and secretion of pro-inflammatory cytokines (Labbe and Saleh, 2008; Salminen et al., 2008) to activate the full cytokine cascade. Limited data is starting to become available regarding the role of inflammasome activation in CNS injury (de Rivero Vaccari et al., 2014). "
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    ABSTRACT: Microglia are critical nervous system-specific immune cells serving as tissue resident macrophages influencing brain development, maintenance of the neural environment, response to injury, and repair. As influenced by their environment, microglia assume a diversity of phenotypes and retain the capability to shift functions to maintain tissue homeostasis. In comparison to peripheral macrophages, microglia demonstrate similar and unique features with regards to phenotype polarization, allowing for innate immunological functions. Microglia can be stimulated by lipopolysaccharide or interferon gamma to a M1 phenotype for expression of pro-inflammatory cytokines or by IL4/IL13 to a M2 phenotype for resolution of inflammation and tissue repair. Increasing evidence suggests a role of metabolic reprogramming in the regulation of the innate inflammatory response. Studies using peripheral immune cells demonstrate that polarization to an M1 phenotype is often accompanied by a shift in cells from oxidative phosphorylation to aerobic glycolysis for energy production. More recently, the link between polarization and mitochondrial energy metabolism has been considered in microglia. Under these conditions, energy demands would be associated with functional activities and cell survival and thus, may serve to influence the contribution of microglia activation to various neurodegenerative conditions. This review examines the polarization states of microglia and the relationship to mitochondrial metabolism. Additional supporting experimental data is provided to demonstrate mitochondrial metabolic shifts in primary microglia and the BV-2 microglia cell line induced under LPS (M1) and IL-4/IL13 (M2) polarization. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 03/2015; DOI:10.1111/bph.13139 · 4.84 Impact Factor
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    • "This process requires the assembly of the cytoplasmic multiprotein complex called an inflammasome [22], responsible for the caspase-1-dependent cleavage and release of the biologically active, mature IL- 1í µí»½. The most studied one is the NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome which may be triggered by diverse stimuli, including PAMPs, toxins, or damage-associated molecular patterns (DAMPs) [23]. Although inflammation has always been considered as an important mechanism in APS, only few data are available on the molecular processes that lead to the inflammation. "
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    ABSTRACT: Antiphospholipid syndrome (APS) is an acquired autoimmune disorder characterized by recurrent thrombosis and pregnancy morbidity in association with the presence of antiphospholipid antibodies. Growing evidence supports the involvement of monocytes in APS pathogenesis. Inflammatory activation of monocytes promotes thrombus formation and other APS complications. However, mechanisms underlying their activation are poorly investigated. We aimed to determine transcriptional activity of monocytes after exposing them to low concentrations of lipopolysaccharide (LPS) and LPS + adenosine triphosphate (ATP) using comparative qRT-PCR. The results showed that LPS significantly increased transcriptional levels of TLR2, IL-23, CCL2, CXCL10, IL-1β, and IL-6 in APS cells, while, in cells from healthy donors, LPS resulted in IL-6 and STAT3 elevated mRNAs. Double stimulation of the cells resulted in decreased mRNA levels of NLRP3 in monocytes isolated from healthy donors and CCL2, IL-1β in APS cells. By contrast, TLR2 mRNAs were elevated in both investigated groups after culture of the cells with LPS + ATP. Thus, the findings indicate increased sensitivity of APS cells to LPS that may contribute to thrombus formation and enhance development or progression of autoimmune processes. Low concentrations of ATP diminish LPS-induced inflammatory state of APS monocytes which might be a potential mechanism which regulates inflammatory state of the cells.
    02/2015; 2015:1-9. DOI:10.1155/2015/292851
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