Mitochondrial NLRP3 Protein Induces Reactive Oxygen Species to Promote Smad Protein Signaling and Fibrosis Independent from the Inflammasome

Bracey, Nathan A.; Gershkovich, Benjamin; Chun, Justin; Vilaysane, Akosua; Meijndert, H. Christopher; Wright, James R.; Fedak, Paul W.M.; Beck, Paul L.; Muruve, Daniel A.; Duff, Henry J.

doi:10.1074/jbc.m114.550624

Cited by 125 publications

(124 citation statements)

References 37 publications

(50 reference statements)

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“…Studies were performed in HPTC as antibodies for Nlrp3, in our hands, perform poorly for immunofluorescence microscopy in TEC. Similar to reports in macrophages and cardiac fibroblasts, [27][28][29] NLRP3 localized primarily to mitochondria in unstimulated HPTC ( Figure 4a). There was no shift in NLRP3 localization between control and TNFα/CHX-stimulated cells, although 'speck-like' NLRP3-positive aggregates at the mitochondria could be observed following treatment.…”

Section: Resultssupporting

confidence: 86%

NLRP3 regulates a non-canonical platform for caspase-8 activation during epithelial cell apoptosis

et al. 2016

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Nod-like receptor, pyrin containing 3 (NLRP3) is characterized primarily as a canonical caspase-1 activating inflammasome in macrophages. NLRP3 is also expressed in the epithelium of the kidney and gut; however, its function remains largely undefined. Primary mouse tubular epithelial cells (TEC) lacking Nlrp3 displayed reduced apoptosis downstream of the tumor necrosis factor (TNF) receptor and CD95. TECs were identified as type II apoptotic cells that activated caspase-8, tBid and mitochondrial apoptosis via caspase-9, responses that were reduced in Nlrp3 − / − cells. The activation of caspase-8 during extrinsic apoptosis induced by TNFα/cycloheximide (TNFα/CHX) was dependent on adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC) and completely independent of caspase-1 or caspase-11. TECs and primary human proximal tubular epithelial cells (HPTC) did not activate a canonical inflammasome, caspase-1, or IL-1β secretion in response to TNFα/CHX or NLRP3-dependent triggers, such as ATP or nigericin. In cell fractionation studies and by confocal microscopy, NLRP3 colocalized with ASC and caspase-8 in speck-like complexes at the mitochondria during apoptosis. The formation of NLRP3/ASC/caspase-8 specks in response to TNFα/ CHX was downstream of TNFR signaling and dependent on potassium efflux. Epithelial ASC specks were present in enteroids undergoing apoptosis and in the injured tubules of wild-type but not Nlrp3 − / − or ASC − / − mice following ureteric unilateral obstruction in vivo. These data show that NLRP3 and ASC form a conserved non-canonical platform for caspase-8 activation, independent of the inflammasome that regulates apoptosis within epithelial cells.

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Section: Resultssupporting

confidence: 86%

NLRP3 regulates a non-canonical platform for caspase-8 activation during epithelial cell apoptosis

et al. 2016

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“…[6][7][8]53 Thus, in myocardial fibroblasts, Nlrp3 induces mitochondrial ROS and Smad signaling directly through its NACHT domain. 53 Likewise, in renal IRI, Nlrp3 conveys tissue damage independent of ASC and cytokine production. 54 Whether aPC regulates the canonical Nlrp3 activation pathway, the noncanonical Nlrp3 activation via caspase-11, or both needs to be further evaluated in future studies.…”

mentioning

confidence: 99%

Cytoprotective activated protein C averts Nlrp3 inflammasome–induced ischemia-reperfusion injury via mTORC1 inhibition

Nazir

Gadi

Al‐Dabet

et al. 2017

Blood

138

129

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“…A pivotal role for the NLRP3 inflammasome in CF for induction of myocardial dysfunction in sepsis has also recently been reported [132]. Additionally, a novel inflammasome-independent role for NLRP3 in CF was recently described in which mitochondrial NLRP3 was found to be important for driving fibrotic responses after Ang II administration including myofibroblast transdifferentiation and fibrosis [76].…”

Section: Nod-like Receptors and The Inflammasomementioning

confidence: 83%

“…However, there is evidence for functional expression of TLR2 [57,73], TLR3 [73], TLR4 [68,73,74] and TLR9 [73,75] in CF. Of the known members of the NLR family, CF express NOD1 and NOD2 [26,62], as well as the inflammasome-associated NLRP3 [73,76] RAGE is expressed in several cell types within the heart [64] and in cultured human and rodent CF [23,[77][78][79].…”

Section: Damp Receptor Expression In Cardiac Fibroblastsmentioning

confidence: 99%

“…CF express NLRP3 [73,76] and studies on ASC and caspase-1 knockout mice have revealed an essential role for the inflammasome in fibroblasts, but not cardiomyocytes, in the initial inflammatory response to myocardial ischaemia/reperfusion injury [131]. Furthermore, NLRP3 in CF has been shown to be important for producing IL-1 in response to extracellular ATP from damaged cardiomyocytes [73].…”

Section: Nod-like Receptors and The Inflammasomementioning

confidence: 99%

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Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs)

Turner

2016

Journal of Molecular and Cellular Cardiology

166

124

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Cardiac fibroblasts (CF) are well-established as key regulators of extracellular matrix (ECM) turnover in the context of myocardial remodelling and fibrosis. Recently, this cell type has also been shown to act as a sensor of myocardial damage by detecting and responding to damage-associated molecular patterns (DAMPs) upregulated with cardiac injury. CF express a range of innate immunity pattern recognition receptors (TLRs, NLRs, IL-1R1, RAGE) that are stimulated by a host of different DAMPs that are evident in the injured or remodelling myocardium. These include intracellular molecules released by necrotic cells (heat shock proteins, high mobility group box 1 protein, S100 proteins), proinflammatory cytokines (interleukin-1), specific ECM molecules up-regulated in response to tissue injury (fibronectin-EDA, tenascin-C) or molecules modified by a pathological environment (advanced glycation end product-modified proteins observed with diabetes). DAMP receptor activation on fibroblasts is coupled to altered cellular function including changes in proliferation, migration, myofibroblast transdifferentiation, ECM turnover and production of fibrotic and inflammatory paracrine factors, which directly impact on the heart's ability to respond to injury. This review gives an overview of the important role played by CF in responding to myocardial DAMPs and how the DAMP/CF axis could be exploited experimentally and therapeutically.3

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Mitochondrial NLRP3 Protein Induces Reactive Oxygen Species to Promote Smad Protein Signaling and Fibrosis Independent from the Inflammasome

Cited by 125 publications

References 37 publications

NLRP3 regulates a non-canonical platform for caspase-8 activation during epithelial cell apoptosis

NLRP3 regulates a non-canonical platform for caspase-8 activation during epithelial cell apoptosis

Cytoprotective activated protein C averts Nlrp3 inflammasome–induced ischemia-reperfusion injury via mTORC1 inhibition

Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs)

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