Superoxide dismutase 1 regulates caspase-1 and endotoxic shock. Nat Immunol 9:866-872

Department of Cellular Microbiology, Max Planck Institute for Infection Biology, 10117 Berlin, Germany.
Nature Immunology (Impact Factor: 20). 08/2008; 9(8):866-72. DOI: 10.1038/ni.1633
Source: PubMed


Caspase-1 serves an essential function in the initiation of inflammation by proteolytically maturing the cytokines interleukin 1 beta and interleukin 18. Several Nod-like receptors activate caspase-1 in response to microbial and 'danger' signals by assembling cytosolic protein complexes called 'inflammasomes'. We show here that superoxide dismutase 1 (SOD1) regulates caspase-1 activation. In SOD1-deficient macrophages, higher superoxide production decreased the cellular redox potential and specifically inhibited caspase-1 by reversible oxidation and glutathionylation of the redox-sensitive cysteine residues Cys397 and Cys362. Conversely, hypoxic conditions abrogated caspase-1 inhibition. In vivo, SOD1-deficient mice produced less caspase-1-dependent cytokines and were less susceptible to lipopolysaccharide-induced septic shock. Our findings identify a physiological post-translational mechanism in the control of caspase-1-mediated inflammatory processes.

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Available from: Felix Meissner, Sep 25, 2014
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    • "Interestingly, activation of the inflammasome involves an AMPK-and UNC-51-like autophagy activating kinase 1 (ULK1)- dependent autophagy pathway and propagation of reactive oxygen species (ROS) (Wen et al. 2011) (Fig. 1). Even though ROS have been considered as important NLRP3-inflammasome activators, they were also shown to inhibit caspase-1 activation through redox signalling (Meissner et al. 2008). Thus, other potent NLRP3- inflammasome-stimulating mechanisms such as K + -efflux, cathepsin B or lysosome rupture (Tschopp and Schroder 2010) need to be considered in the future in the context of metabolic inflammation. "
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    ABSTRACT: Low-grade inflammation is an established pathological condition that contributes to the development of obesity, insulin resistance and type 2 diabetes. Metabolic inflammation is dependent on multiple signalling events. In an overnutrition state, canonical inflammatory pathways are induced by inflammatory cytokines and lipid species. They can also be triggered through inflammasome activation as well as through cellular stress provoked by the unfolded protein response at the endoplasmic reticulum as well as by reactive oxygen species. In this chapter, we summarize the current knowledge about signalling events within the cell and describe how they impact on metabolic inflammation and whole-body metabolism. We particularly highlight the interplay between different signalling pathways that link low-grade inflammation responses to the inactivation of the insulin receptor pathway, ultimately leading to insulin resistance, a hallmark of type 2 diabetes.
    Handbook of experimental pharmacology 04/2015; DOI:10.1007/164_2015_4
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    • "Another mechanism proposed to mediate the activation of the NLRP3 inflammasome is the enhanced formation of intracellular ROS [20], [41]. However, the role of ROS has been challenged [42], [43] and the overproduction of ROS has been shown also to inhibit the activation of caspase-1 [44]. Since ethanol treatment increases oxidative stress and induces the generation of ROS in several cell types [45], [46], we examined whether the enhanced ROS production, induced by ethanol, could contribute to the inhibitory effect of ethanol. "
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    ABSTRACT: In the pathogenesis of coronary atherosclerosis, local macrophage-driven inflammation and secretion of proinflammatory cytokines, interleukin-1β (IL-1β) in particular, are recognized as key factors. Moderate alcohol consumption is associated with a reduced risk of coronary artery disease mortality. Here we examined in cultured human macrophages whether ethanol modulates the intracellular processes involved in the secretion of IL-1β. Ethanol decreased dose-dependently the production of mature IL-1β induced by activators of the NLRP3 inflammasome, i.e. ATP, cholesterol crystals, serum amyloid A and nigericin. Ethanol had no significant effect on the expression of NLRP3 or IL1B mRNA in LPS-primed macrophages. Moreover, secretion of IL-1β was decreased in parallel with reduction of caspase-1 activation, demonstrating that ethanol inhibits inflammasome activation instead of synthesis of pro-IL-1β. Acetaldehyde, a highly reactive metabolite of ethanol, had no effect on the ATP-induced IL-1β secretion. Ethanol also attenuated the secretion of IL-1β triggered by synthetic double-stranded DNA, an activator of the AIM2 inflammasome. Ethanol conferred the inhibitory functions by attenuating the disruption of lysosomal integrity and ensuing leakage of the lysosomal protease cathepsin B and by reducing oligomerization of ASC. Ethanol-induced inhibition of the NLRP3 inflammasome activation in macrophages may represent a biological pathway underlying the protective effect of moderate alcohol consumption on coronary heart disease.
    PLoS ONE 11/2013; 8(11):e78537. DOI:10.1371/journal.pone.0078537 · 3.23 Impact Factor
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    • "However, all of them seem to be switched on by cellular stress due to changes in environmental conditions (Giuliani et al., 2011). This is true both for the passive release by dying cells exploited by IL-1α and IL-33, since death represents the last step of a cell subjected to stress, and for the more complex secretion of IL-1β and IL-18 that are regulated by redox stress (Cruz et al., 2007; Dostert et al., 2008; Hewinson et al., 2008; Meissner et al., 2008; Tassi et al., 2009). Interestingly, both purinergic receptor stimulation and mechanical stress, cause a disturbance of redox homeostasis resulting in redox response (Wu et al., 2013); redox response is also required for inflammasome activation (Rubartelli, 2012). "
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    ABSTRACT: Intercellular communications control fundamental biological processes required for the survival of multicellular organisms. Secretory proteins are among the most important messengers in this network of information. Proteins destined to the extracellular environment contain a signal sequence with the necessary information to target them to the Endoplasmic Reticulum, and are released by a "classical" pathway of secretion. However, in the early 1990s it became evident that non-classical mechanisms must exist for the secretion of some proteins, which in spite of their extracellular localization and function, lack a signal peptide. Indeed, the group of leaderless secretory proteins rapidly grew and is still growing. Many of them are implicated in the regulation of the inflammatory response. Interestingly, most members of the IL-1 family (IL-1F), including the master pro-inflammatory cytokine IL-1β, are leaderless proteins and find their way out of the cells in different manners. In this article, we will review current hypotheses on the mechanisms of externalization of IL-1F members and discuss their relevance with respect to the different functions (as cytokines or as DAMPs) played by the different IL-1 proteins.
    Frontiers in Immunology 05/2013; 4:123. DOI:10.3389/fimmu.2013.00123
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