The role of mitochondria in NLRP3 inflammasome activation

Liu, Qiuyun; Zhang, Danyan; Hu, Diyu; Zhou, Xiangmei; Zhou, Yang

doi:10.1016/j.molimm.2018.09.010

Cited by 364 publications

(254 citation statements)

References 136 publications

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“…132 In addition, reactive oxygen species and oxidized mitochondrial DNA have been shown to activate the NLRP3 inflammasome, highlighting the importance of the mitochondria in NLRP3 activation. [123][124][125]133,134 Recently, disruption of the trans-Golgi network (TGN) has been described as a cellular event capable of activating NLRP3 in response to potassium-dependent and potassium-independent NLRP3 activators. 135 The authors found that a polybasic stretch of four lysine residues on NLRP3 mediated charge-based interactions with phosphatidylinositol-4-phosphate, a component of the TGN.…”

Section: Activation Of Nlrp3mentioning

confidence: 99%

Toward targeting inflammasomes: insights into their regulation and activation

2020

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Inflammasomes are multi-component signaling complexes critical to the initiation of pyroptotic cell death in response to invading pathogens and cellular damage. A number of innate immune receptors have been reported to serve as inflammasome sensors. Activation of these sensors leads to the proteolytic activation of caspase-1, a proinflammatory caspase responsible for the cleavage of proinflammatory cytokines interleukin-1β and interleukin-18 and the effector of pyroptotic cell death, gasdermin D. Though crucial to the innate immune response to infection, dysregulation of inflammasome activation can lead to the development of inflammatory diseases, neurodegeneration, and cancer. Therefore, clinical interest in the modulation of inflammasome activation is swiftly growing. As such, it is imperative to develop a mechanistic understanding of the regulation of these complexes. In this review, we divide the regulation of inflammasome activation into three parts. We discuss the transcriptional regulation of inflammasome components and related proteins, the post-translational mechanisms of inflammasome activation, and advances in the understanding of the structural basis of inflammasome activation.

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Section: Activation Of Nlrp3mentioning

confidence: 99%

Toward targeting inflammasomes: insights into their regulation and activation

2020

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“…A growing body of evidence suggests that the MSU crystal-induced differentiation of monocytes into macrophages is associated with the initiation, progression and resolution of acute gouty inflammation (5,37). In addition, it was reported that MSU crystals increase the secretion of cytokines and chemokines, including TNF-α, il-1β, il-18, il-6, and il-8, by macrophages and monocytes (38)(39)(40). IL-1β and TnF-α have been implicated in the development of gout flare-ups (41).…”

Section: Discussionmentioning

confidence: 99%

Total saponin of Dioscorea�collettii attenuates MSU crystal‑induced inflammation via inhibiting the activation of the NALP3 inflammasome and caspase‑1 in THP‑1 macrophages

et al. 2020

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Total saponins extracted from Dioscorea collettii (TSd), extracts of the chinese herb Dioscorea, are thought to exhibit therapeutic benefit in gouty arthritis. However, its exact mechanism remains unclear. The current study aimed to elucidate the underlying mechanisms by investigating the effects of TSD on the inflammation induced by monosodium urate (MSU) crystals in THP-1 macrophages. The viability of THP-1 macrophages was examined using the MTT assay and the levels of inflammatory cytokines, including interleukin (IL)-1β, il-18 and tumor necrosis factor (TnF)-α, released by the cells were quantitatively measured using ELISA kits. The results revealed that the protein level of cluster of differentiation 11b increased in THP-1 cells treated with 100 ng/ml phorbol ester, suggesting that monocytic THP-1 cells were successfully differentiated into macrophages. TSD decreased the levels of inflammatory cytokines, including TnF-α, il-18 and il-1β, secreted by THP-1 macrophages. As the release of IL-1β and il-18 is dependent on the NLR family pyrin domain containing 3 (NALP3) inflammasome and caspase-1, the current study investigated the effect of TSD on the aforementioned proteins. The results revealed that TSD decreased the protein levels of NALP3 and apoptosis-associated speck-like, which serve important roles in the assembly of the NALP3 inflammasome. Furthermore, NALP3 inflammasome-related proteins were also decreased by TSD in rotenone induced THP-1 macrophages, TSD inhibited the activation of caspase-1 and rotenone-induced NALP3 inflammasome activation in THP-1 macrophages. The results obtained in the current study revealed that TSD attenuated MSU crystal-induced inflammation by inhibiting rotenone-induced activation of the NALP3 inflammasome and caspase-1, suggesting that these two proteins may be novel targets for the treatment of gouty arthritis.

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“…Pathogenassociated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) such as lipopolysaccharide (LPS), asbestos, ATP and uric acid activate NLR family pyrin domain containing 3 (NLRP3) inflammasome via mROS generation [155,156]. Pharmacologic or genetic inhibition of autophagy elevates mROS concentration, which heightens inflammasome activation [157,158]. Increase of mROS persuades lysosomal membrane permeabilization, which is required for NLRP3 activation [159].…”

Section: Immunitymentioning

confidence: 99%

Physiological Functions of Mitochondrial Reactive Oxygen Species

Choi¹,

Kim²

2020

Free Radical Medicine and Biology

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Mitochondria are the major energy producers within a cell in the form of adenosine triphosphate by oxidative phosphorylation. Normal mitochondrial metabolism inevitably generates reactive oxygen species (ROS), which have been considered to solely cause cellular damage. Increase of oxidative stress has been linked to various pathologies. Thus, mitochondrial ROS (mROS) were basically proposed as byproducts of oxidative metabolism, which undergo normalized by antioxidant enzymes. However, the mROS have extensively been esteemed to function as signalling molecules to regulate a wide variety of physiology. These phenomena are indeed dependent on mitochondrial redox status, which is dynamically altered under different physiological and pathological conditions. The oxidative stress is incurred by which the redox status is inclined to exceeded oxidation or reduction. Here, we attempt to integrate the recent advances in our understanding of the physiological functions of mROS.Keywords: mitochondrial ROS, oxidative stress, oxidative metabolism, redox signaling, mitochondrial physiology Free Radical Medicine and Biology 2 reactive metabolites of O 2 , including superoxide anion (O 2 ·− ) and hydrogen peroxide (H 2 O 2 ), formed by one-and two-electron reductions of O 2 , respectively [7].In the presence of transition metal ions, the more reactive hydroxyl radical (OH · ) is formed. The O 2 ·− is rapidly dismutated to H 2 O 2 by two dismutases including Cu/ Zn-superoxide dismutase (Cu/ZnSOD) in mitochondrial intermembrane space and manganese-dependent superoxide dismutase (MnSOD) in mitochondrial matrix. Unless the dismutation of O 2 ·− is catalyzed into H 2 O 2 , the radical oxidant promotes DNA damage, protein oxidation and lipid peroxidation in many types of cells. H 2 O 2 is also cell damaging molecule to be degraded to water by catalase [8]. Although the O 2 ·− generation by respiratory complexes is a well-established phenomenon, it is still poorly understood in mechanism [9].Mitochondria have been implicated in the regulation of a number of physiological and pathological processes, including proliferation, differentiation, programmed cell death, innate immunity, autophagy, redox signalling, calcium homeostasis, hypoxic stress responses and stem cell reprogramming [10][11][12][13][14][15][16]. The mROS production contributes to mitochondrial damage in a range of pathologies, which is also is closely related to redox signalling in the cell [4,17]. However, accumulating evidences show that mROS are not only deleterious molecules derived from the cellular metabolism but also indispensable participants in diverse cellular signalling and regulations [18][19][20].In this chapter, we briefly summarize recent developments in our understanding of the involvement of mROS as signalling mediators in redox biology, rather than pathological stress, underlying physiological conditions.

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The role of mitochondria in NLRP3 inflammasome activation

Cited by 364 publications

References 136 publications

Toward targeting inflammasomes: insights into their regulation and activation

Toward targeting inflammasomes: insights into their regulation and activation

Total saponin of Dioscorea�collettii attenuates MSU crystal‑induced inflammation via inhibiting the activation of the NALP3 inflammasome and caspase‑1 in THP‑1 macrophages

Physiological Functions of Mitochondrial Reactive Oxygen Species

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