Oxidized Mitochondrial DNA Activates the NLRP3 Inflammasome during Apoptosis

Shimada, Kenichi; Crother, Timothy R.; Karlin, Justin; Dagvadorj, Jargalsaikhan; Chiba, Norika; Chen, Shuang; Ramanujan, V. Krishnan; Wolf, Andrea J.; Vergnes, Laurent; Ojcius, David M.; Rentsendorj, Altan; Vargas, Mario H.; Guerrero, Candace R.; Wang, Yinsheng; Fitzgerald, Katherine A.; Underhill, David; Town, Terrence; Arditi, Moshe

doi:10.1016/j.immuni.2012.01.009

Cited by 1,671 publications

(1,507 citation statements)

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“…63 Moreover, multiple NLRP3-triggering agents leading to mitochondrial dysfunction and cell death result in the cytosolic increase of oxidized mitochondrial DNA, which, in turn, appears to bind to NLRP3 and to activate the NLRP3 inflammasome complex. 71 However, both mitochondrial ROS-dependent and -independent pathways are required for NLRP3 inflammasome activation triggered by serum amyloid A. 72 Another recent study suggested that ROS-dependent and -independent NLRP3 activators cause mitochondrial destabilization and dysfunction, thereby promoting NLRP3 inflammasome activation.…”

Section: Molecular Mechanisms Of the Canonical Activation Of The Nlrpmentioning

confidence: 99%

Molecular mechanisms regulating NLRP3 inflammasome activation

et al. 2015

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Section: Molecular Mechanisms Of the Canonical Activation Of The Nlrpmentioning

confidence: 99%

Molecular mechanisms regulating NLRP3 inflammasome activation

et al. 2015

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“…Of note, pyroptosis (cell death resulting from unfettered inflammasome activation) and apoptosis are not exclusive, and pathways leading to or triggered by these cell-death forms interact. 6,25,26 Furthermore, we do not exclude a role of mitochondrial dysfunction. Indeed, mitochondrial dysfunction promotes inflammasome activation via increased ROS, thus contributing to glomerular dysfunction.…”

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confidence: 93%

Caspase-1, but Not Caspase-3, Promotes Diabetic Nephropathy

Shahzad

Bock

Al‐Dabet

et al. 2016

JASN

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Glomerular apoptosis may contribute to diabetic nephropathy (dNP), but the pathophysiologic relevance of this process remains obscure. Here, we administered two partially disjunct polycaspase inhibitors in 8-week-old diabetic (db/db) mice: M-920 (inhibiting caspase-1, -3, -4, -5, -6, -7, and -8) and CIX (inhibiting caspase-3, -6, -7, -8, and -10). Notably, despite reduction in glomerular cell death and caspase-3 activity by both inhibitors, only M-920 ameliorated dNP. Nephroprotection by M-920 was associated with reduced renal caspase-1 and inflammasome activity. Accordingly, analysis of gene expression data in the Nephromine database revealed persistently elevated glomerular expression of inflammasome markers (NLRP3, CASP1, PYCARD, IL-18, IL-1b), but not of apoptosis markers (CASP3, CASP7, PARP1), in patients with and murine models of dNP. In vitro, increased levels of markers of inflammasome activation (Nlrp3, caspase-1 cleavage) preceded those of markers of apoptosis activation (caspase-3 and -7, PARP1 cleavage) in glucosestressed podocytes. Finally, caspase-3 deficiency did not protect mice from dNP, whereas both homozygous and hemizygous caspase-1 deficiency did. Hence, these results suggest caspase-3-dependent cell death has a negligible effect, whereas caspase-1-dependent inflammasome activation has a crucial function in the establishment of dNP. Furthermore, small molecules targeting caspase-1 or inflammasome activation may be a feasible therapeutic approach in dNP.

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“…These results suggest that some signal/s common to all of these activators must be recognized. Currently, these common denominators are thought to be K + efflux [6,7], lysosomal damage and the release of Cathepsins [8,9], mitochondrial ROS production and the release of oxidized mitochondrial DNA [10,11]. Nevertheless, despite these advances it remains unclear if and how these events are causally linked.…”

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confidence: 99%

Caspase‐11 activates a canonical NLRP3 inflammasome by promoting K⁺ efflux

2015

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Recognition of microbe-associated molecular patterns or endogenous danger signals by a subset of cytosolic PRRs results in the assembly of multiprotein signaling complexes, the so-called inflammasomes. Canonical inflammasomes are assembled by NOD-like receptor (NLR) or PYHIN family members and activate caspase-1, which promotes the induction of pyroptosis and the release of mature interleukin-1β/-18. Recently, a noncanonical inflammasome pathway was discovered that results in caspase-11 activation in response to bacterial lipopolysaccharide (LPS) in the cytosol. Interestingly, caspase-11 induces pyroptosis by itself, but requires NLRP3, the inflammasome adapter ASC, and caspase-1 to promote cytokine secretion. Here, we have studied the mechanism by which caspase-11 controls IL-1β secretion. Investigating NLRP3/ASC complex formation, we find that caspase-11 functions upstream of a canonical NLRP3 inflammasome. The activation of NLRP3 by caspase-11 during LPS transfection is a cell-intrinsic process and is independent of the release of danger signals. Furthermore, we show that active caspase-11 leads to a drop of intracellular potassium levels, which is necessary to activate NLRP3. Our study, therefore, sheds new light on the mechanism of noncanonical inflammasome signaling. Additional supporting information may be found in the online version of this article at the publisher's web-site Keywords IntroductionInflammasomes are multiprotein complexes assembled by cytosolic PRRs from the NOD-like receptor (NLR) and PYHIN protein family upon recognition of microbe-associated molecular patterns (MAMPs) or danger signals [1]. Ligand recognition results in receptor activation and recruitment of the adaptor ASC, which rapidly oligomerizes to form the so-called ASC speck. The ASC speck serves as an activation platform for the cysteine protease Immunol. 2015Immunol. . 45: 2927Immunol. -2936 it remains unclear how the stimulus is recognized. This is particularly true for the NLRP3 inflammasome that is activated by a variety of structurally and chemically distinct stimuli, ranging from pathogens and pore-forming toxin to crystalline particles and UV irradiation [5]. These results suggest that some signal/s common to all of these activators must be recognized. Currently, these common denominators are thought to be K + efflux [6,7], lysosomal damage and the release of Cathepsins [8,9], mitochondrial ROS production and the release of oxidized mitochondrial DNA [10,11]. Nevertheless, despite these advances it remains unclear if and how these events are causally linked. Investigating the response of murine macrophages to lipopolysaccharide (LPS) and cholera toxin B, as well as other bacterial inflammasome activators, Kayagaki et al. recently discovered a noncanonical inflammasome pathway that relies on caspase-11 [12]. Subsequent studies reported that this pathway was activated by Gram-negative, but not by Gram-positive, bacteria, indicating a requirement for a conserved factor from Gram-negative bacteria [13,14]. Consistently, i...

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Oxidized Mitochondrial DNA Activates the NLRP3 Inflammasome during Apoptosis

Cited by 1,671 publications

References 51 publications

Molecular mechanisms regulating NLRP3 inflammasome activation

Molecular mechanisms regulating NLRP3 inflammasome activation

Caspase-1, but Not Caspase-3, Promotes Diabetic Nephropathy

Caspase‐11 activates a canonical NLRP3 inflammasome by promoting K⁺ efflux

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Oxidized Mitochondrial DNA Activates the NLRP3 Inflammasome during Apoptosis

Cited by 1,671 publications

References 51 publications

Molecular mechanisms regulating NLRP3 inflammasome activation

Molecular mechanisms regulating NLRP3 inflammasome activation

Caspase-1, but Not Caspase-3, Promotes Diabetic Nephropathy

Caspase‐11 activates a canonical NLRP3 inflammasome by promoting K+ efflux

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Product

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Caspase‐11 activates a canonical NLRP3 inflammasome by promoting K⁺ efflux