Martinon F, Tschopp J.. Inflammatory caspases and inflammasomes: master switches of inflammation. Cell Death Differ 14: 10-22

Department of Biochemistry, University of Lausanne, BIL Biomedical Research Center, Epalinges, Switzerland.
Cell Death and Differentiation (Impact Factor: 8.18). 02/2007; 14(1):10-22. DOI: 10.1038/sj.cdd.4402038
Source: PubMed


Fifteen years have passed since the cloning and characterization of the interleukin-1beta-converting enzyme (ICE/caspase-1), the first identified member of a family of proteases currently known as caspases. Caspase-1 is the prototypical member of a subclass of caspases involved in cytokine maturation termed inflammatory caspases that also include caspase-4 caspase -5, caspase -11 and caspase -12. Efforts to elucidate the molecular mechanisms involved in the activation of these proteases have uncovered an important role for the NLR family members, NALPs, NAIP and IPAF. These proteins promote the assembly of multiprotein complexes termed inflammasomes, which are required for activation of inflammatory caspases. This article will review some evolutionary aspects, biochemical evidences and genetic studies, underlining the role of inflammasomes and inflammatory caspases in innate immunity against pathogens, autoinflammatory syndromes and in the biology of reproduction.

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Available from: Fabio Martinon, Feb 10, 2015
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    • "Keeping in mind that inflammasome participation was first associated with auto-inflammatory syndromes and defense strategies against pathogens [73], the present knowledge about the involvement of inflammasomes in neurological and psychiatric disorders, either acute or chronic, has substantially broadened in the past years, thus opening a new window for therapeutic strategies in the treatment of brain disorders. "
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    ABSTRACT: Neuroinflammation in the central nervous system is triggered by toxic stimuli or degenerative events, orchestrates the interplay of brain-intrinsic immune cells and neighboring neural cells, and sequentially allows leukocyte extravasation from the periphery into the brain parenchyma. During the inflammatory cascade, immune-competent cells become activated and secrete a plethora of cytokines and chemokines which form a local inflammatory signaling network important for warding off harmful stimuli to the host but are likewise necessary to preserve damaged brain tissue. Inflammatory responses are initiated by extra- and intracellular pathogen and danger-associated receptors. These signals are processed by multi-protein complexes termed inflammasomes which trigger the production of biologically active interleukins-1 and 18 after the cleavage of caspase-1. Estrogens and progesterone are neuroprotective and anti-inflammatory in diverse disease models of the brain in particular under acute inflammatory conditions such as stroke and traumatic brain injury. Both steroids are able to attenuate pro-inflammatory cytokine activity. Recent literature and our own studies provide convincing evidence that the anti-inflammatory potency of these steroids result from a complex interaction with the inflammasome activation and their up-stream regulatory network of miRNAs in brain-intrinsic innate immune cells. This article examines steroid-inflammasome interactions in the brain during brain injury and illuminates the importance of regulation initial upstream events during neuroinflammation. Copyright © 2015. Published by Elsevier Ltd.
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    • "IL-1í µí»½ lacks a secretory signal peptide and is secreted through a nonclassical pathway [19], and there is a need for a secondary stimulus, such as endogenous adenosine triphosphate (ATP), to promote posttranslational processing of IL-1í µí»½ [20] [21]. 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]. "
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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.
    Full-text · Article · Feb 2015
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    • "Therapy consists primarily of administering IL-1β inhibitors such as anakinra, indicating that NLRP3 has a key regulatory role in managing IL-1β (Dowds et al., 2004). NLRP3 recognizes a very diverse range of inflammatory mediators, including monosodium urate (Martinon et al., 2006), asbestos, silica (Dostert et al., 2008), and low intracellular potassium (Pétrilli et al., 2007), along with a large array of microbial triggers, which show specific activation profiles (Martinon and Tschopp, 2007). A growing number of microbial sources and their toxins seem to either activate or regulate the NLRP3 inflammasome including Mycobacterium tuberculosis protein ESAT- 6 (Mishra et al., 2010), Candida albicans (Hise et al., 2009), Stapyloccocus aureus alpha hemolysin (Craven et al., 2009), Pseudomonas aeruginosa pilin (Arlehamn and Evans, 2011), Streptococcus pyogenes (Harder et al., 2009), HIV-1 (Guo et al., 2014), and adenovirus type 5 (Barlan et al., 2011), among others. "
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    ABSTRACT: Gardnerella vaginalis is a Gram-positive bacterium associated with bacterial vaginosis (BV), pelvic inflammatory disease, and preterm birth. BV is the most prevalent vaginal infection in women, characterized by the absence of normal Lactobacilli and overgrowth of G. vaginalis and other bacterial species. This study tested the hypothesis that G. vaginalis induces an inflammatory response in the human cell line, THP-1. The objectives of the study were to 1) determine whether different strains of G. vaginalis cause proinflammatory cytokinesproduction in THP-1 cells, 2) characterize intracellular pathways by which these cytokines are produced, and 3) determine molecular mechanisms involved in death of cells treated with strains of G. vaginalis. In these studies, G. vaginalis strain 14018 induced statisticaliy significant increases in the inflammasome-dependent cytokines IL-1β, IL-18, as well as TNF-α in THP-1 monocytes. This same strain of G. vaginalis also caused statistically significant cell death in THP-1 monocytes and cleavage of caspase-1 by 24 h following treatment. Knockdown of the inflammasome component, NLRP3, in THP-1 cells reduced secretion of IL-1β. Additionally, THP-1 cells stably expressing ASC with a fluorescent tag exhibited colocalization of NLRP3 with ASC in G. vaginalis-treated THP-1 cells. These studies confirmed the role of the NLRP3 inflammasome in G. vaginalis inflammation. In a strain-specific study, a statistically significant increase in THP-1 monocyte differentiation and IL-1β secretion were detected in response to G. vaginalis strains 14018 and 49145 but not strain 14019. Cytokine and inflammasome responses were similar for strains 14018 and 49145, but strain 14019 did not induce an inflammatory response in THP-1 cells. The strain-specific ability of G. vaginalis to induce inflammation could con- tribute to the variability observed clinically between women colonized with G. vaginalis. The deleterious effects of G. vaginalis observed in THP-1 monocytes were not observed for the human trophoblast cell line HTR8 when treated with any of the G. vaginalis strains. The results of these studies increase the understanding of how G. vaginal- is activates the innate immune system and suggests that a strain-dependent activation of inflammation may be involved in bacterial vaginosis and preterm birth.
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