K + Efflux-Independent NLRP3 Inflammasome Activation by Small Molecules Targeting Mitochondria

Groß, Christina; Mishra, Ritu; Schneider, Katharina S.; Médard, Guillaume; Wettmarshausen, Jennifer; Dittlein, Daniela; Shi, Hao; Gorka, Oliver; Koenig, Paul; Fromm, Stephan; Magnani, Giovanni; Ćiković, Tamara; Hartjes, Lara; Smollich, Joachim; Robertson, Avril A. B.; Cooper, Matthew A.; Schmidt-Supprian, Marc; Schuster, Michael W.; Schroder, Kate; Brož, Petr; Traidl‐Hoffmann, Claudia; Beutler, Bruce; Küster, Bernhard; Ruland, Jürgen; Schneider, Sabine; Perocchi, Fabiana; Groß, Olaf

doi:10.1016/j.immuni.2016.08.010

Cited by 378 publications

(258 citation statements)

References 45 publications

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“…Whether all or only a part of these events are required for NLRP3 inflammasome activation is not clear. Munoz-Planillo et al (2013) suggested that the sole reduction of intracellular K + was sufficient for NLRP3 inflammasome activation but recent reports have suggested that, in certain circumstances, inflammasome activation can occur independently of K + -efflux (Gross et al, 2016) or phagocytosis of bacteria (Chen et al, 2016). Moreover, the activity of the NRLP3 inflammasome has also been reported to be controlled by kinases such as Bruton’s tyrosine kinase (BTK) interacting with NLRP3 and ASC thus favoring the recruitment of caspase-1 (Ito et al, 2015), and JNK or Syk kinases regulating ASC oligomerization (Hara et al, 2013; Okada et al, 2014).…”

Section: The Inflammasomesmentioning

confidence: 99%

Potential of IL-1, IL-18 and Inflammasome Inhibition for the Treatment of Inflammatory Skin Diseases

2017

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In 2002, intracellular protein complexes known as the inflammasomes were discovered and were shown to have a crucial role in the sensing of intracellular pathogen- and danger-associated molecular patterns (PAMPs and DAMPs). Activation of the inflammasomes results in the processing and subsequent secretion of the pro-inflammatory cytokines IL-1β and IL-18. Several autoinflammatory disorders such as cryopyrin-associated periodic syndromes and Familial Mediterranean Fever have been associated with mutations of genes encoding inflammasome components. Moreover, the importance of IL-1 has been reported for an increasing number of autoinflammatory skin diseases including but not limited to deficiency of IL-1 receptor antagonist, mevalonate kinase deficiency and PAPA syndrome. Recent findings have revealed that excessive IL-1 release induced by harmful stimuli likely contributes to the pathogenesis of common dermatological diseases such as acne vulgaris or seborrheic dermatitis. A key pathogenic feature of these diseases is IL-1β-induced neutrophil recruitment to the skin. IL-1β blockade may therefore represent a promising therapeutic approach. Several case reports and clinical trials have demonstrated the efficacy of IL-1 inhibition in the treatment of these skin disorders. Next to the recombinant IL-1 receptor antagonist (IL-1Ra) Anakinra and the soluble decoy Rilonacept, the anti-IL-1α monoclonal antibody MABp1 and anti-IL-1β Canakinumab but also Gevokizumab, LY2189102 and P2D7KK, offer valid alternatives to target IL-1. Although less thoroughly investigated, an involvement of IL-18 in the development of cutaneous inflammatory disorders is also suspected. The present review describes the role of IL-1 in diseases with skin involvement and gives an overview of the relevant studies discussing the therapeutic potential of modulating the secretion and activity of IL-1 and IL-18 in such diseases.

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Section: The Inflammasomesmentioning

confidence: 99%

Potential of IL-1, IL-18 and Inflammasome Inhibition for the Treatment of Inflammatory Skin Diseases

2017

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“…Given the reduced expression of the mitophagy facilitator dynamin-related protein 1 (Drp1) preceding lupus onset [76], accumulation of damaged mitochondria is a likely culprit in disease progression. Furthermore, mitochondrial Complex I dysfunction and subsequent mitochondrial ROS production induced by imiquimod (a TLR7 agonist and mediator of lupus-like disease [77]), led to NLRP3 inflammasome activation in a recent study [78]. As NLRP3 inflammasome activation has been associated with SLE pathogenesis [79], the aforementioned study provides additional evidence potentially linking mitochondrial defects in lupus with downstream proinflammatory cascades that promote disease progression.…”

Section: Role Of Ros In Tissue Damage and Immune Cell Activation In Lmentioning

confidence: 99%

Metabolic abnormalities and oxidative stress in lupus

Lightfoot

Blanco

Kaplan

2017

Current Opinion in Rheumatology

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Purpose of review Upon antigen exposure, immune cells rely on cell-specific metabolic pathways to mount an efficient immune response. In autoimmunity, failure in critical metabolic checkpoints may lead to immune cell hyper-activation and tissue damage. Oxidative stress in autoimmune patients can also contribute to immune dysregulation and injury to the host. Recent insights into the immune cell metabolism signatures specifically associated with systemic lupus erythematosus (SLE) and the consequences of heightened oxidative stress in patients are discussed herein. Recent findings Glucose metabolism inhibitors, mTOR pathway modulators, and PPARγ-activating compounds demonstrate therapeutic benefit in experimental models of lupus. Mitochondrial-derived reactive oxygen species (ROS) and molecular modifications induced by oxidative stress appear to be detrimental in lupus. Effective therapies tailored towards the reconfiguration of metabolic imbalances in lupus immune cells and the reduction of mitochondrial ROS production/availability are currently being tested. Summary A paucity of knowledge exists regarding the metabolic needs of a number of immune cells involved in the pathogenesis of SLE, including myeloid cells and B cells. Nonetheless, SLE-specific metabolic signatures have been identified and their specific targeting, along with mitochondrial ROS inhibitors/scavengers, could show therapeutic advantage in lupus patients.

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“…In the later, mitochondrial manipulation would constitute an approach of choice to facilitate macrophage repolarization (56). Because some mitochondrial metabolites and the use of ETC CI or CII inhibitors can modulate cytokine production (8, 19, 41, 54, 57), such approach seems very promising. Moreover, mitochondrial ROS and metabolites, such as fumarate or itaconate, show a direct microbicidal effect (5, 30, 66).…”

Section: Discussionmentioning

confidence: 99%

“…The use of the CI inhibitors metformin and rotenone decreased mitochondrial ROS production in LPS-activated mouse macrophages thereby reducing IL-1β production and boosting IL-10 production (54). In addition to their function as TLR7 agonists, imiquimod and CL097 also inhibited the quinone oxidoreductases NQO2 and CI, inducing ROS that contributed to NLRP3 activation (57). Conversely, the CII inhibitor dimethyl malonate enhanced the production of IL-1RA and IL-10 and promote an anti-inflammatory response by preventing mitochondrial ROS generation and succinate oxidation (19).…”

Section: Functional Consequences Of Mitochondrial Adaptations In Macrmentioning

confidence: 99%

Innate Immune Function of Mitochondrial Metabolism

2017

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Sensing of microbe-associated molecular patterns or danger signals by innate immune receptors drives a complex exchange of information. Innate receptor signaling not only triggers transcriptional events but also induces profound changes in metabolic fluxes, redox balance, and metabolite abundance thereby influencing immune cell function. Mitochondria are at the core of metabolic adaptation to the changing environment. The close interaction between mitochondrial metabolism and immune signaling has emerged as a central regulator of innate sensing. Metabolic processes generate a constant flow of electrons that eventually end up in the mitochondrial electron transport chain (ETC). Two electron carriers and four respiratory complexes that can assemble as larger molecular supercomplexes compose the ETC in the mitochondrial inner membrane. While the meaning and biological relevance of such structural organization is a matter of passionate debates, recent data support that innate stimuli remodel the ETC. We will review the function of mitochondrial metabolism and ETC dynamics as innate rheostats that regulate signaling, transcription, and epigenetics to orchestrate innate immune responses.

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K + Efflux-Independent NLRP3 Inflammasome Activation by Small Molecules Targeting Mitochondria

Cited by 378 publications

References 45 publications

Potential of IL-1, IL-18 and Inflammasome Inhibition for the Treatment of Inflammatory Skin Diseases

Potential of IL-1, IL-18 and Inflammasome Inhibition for the Treatment of Inflammatory Skin Diseases

Metabolic abnormalities and oxidative stress in lupus

Innate Immune Function of Mitochondrial Metabolism

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