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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    • "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.
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    • "Interruption of ROS production with pharmacological inhibitors blocks activation of the Nlrp3 inflammasome, suggesting that the generation of ROS is a required upstream event for Nlrp3 activation (Cassel et al., 2008; Cruz et al., 2007; Dostert et al., 2008; Pé trilli et al., 2007; Zhou et al., 2011). Recent studies have elucidated the cellular source of the responsible ROS to be of mitochondrial origin and independent of the NADPH oxidases (Meissner et al., 2008; Nakahira et al., 2011; van Bruggen et al., 2010; Zhou et al., 2011). Linezolid belongs to the oxazolidinone class of antibiotics and has been employed in the treatment of infections caused by antibiotic-resistant bacteria, including vancomycin-resistant enterococcus and methicillin-resistant Staphylococcus aureus (Ament et al., 2002), and as part of multidrug regimens in the treatment of mycobacterial infections (Sood et al., 2006). "
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    ABSTRACT: Nlrp3 inflammasome activation occurs in response to numerous agonists but the specific mechanism by which this takes place remains unclear. All previously evaluated activators of the Nlrp3 inflammasome induce the generation of mitochondrial reactive oxygen species (ROS), suggesting a model in which ROS is a required upstream mediator of Nlrp3 inflammasome activation. Here we have identified the oxazolidinone antibiotic linezolid as a Nlrp3 agonist that activates the Nlrp3 inflammasome independently of ROS. The pathways for ROS-dependent and ROS-independent Nlrp3 activation converged upon mitochondrial dysfunction and specifically the mitochondrial lipid cardiolipin. Cardiolipin bound to Nlrp3 directly and interference with cardiolipin synthesis specifically inhibited Nlrp3 inflammasome activation. Together these data suggest that mitochondria play a critical role in the activation of the Nlrp3 inflammasome through the direct binding of Nlrp3 to cardiolipin.
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