Cochlear Marginal Cell Pyroptosis Is Induced by Cisplatin via NLRP3 Inflammasome Activation

Yu, Wei; Zong, Shimin; Zhou, Peng; Wei, Jiahui; Wang, Enhao; Ming, Ruijie; Xiao, Hongjun

doi:10.3389/fimmu.2022.823439

Cited by 11 publications

(11 citation statements)

References 86 publications

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“…The combination of ROS-mediated mitochondrial dysfunction and the NLRP3 in ammasome activation contributes to the progression of neurodegenerative diseases, including SNHL. ROS-induced oxidative stress and NLRP3-activated pro-in ammatory cytokines can disrupt the cochlear structure of auditory hair cells and SGN (Yu et al 2022;Nakanishi et al 2020). The early endosome-dependent mitophagy mediated by APPL1 can limit the activation of NLRP3 in ammasome (Wu and Cheng 2022).…”

Section: Discussionmentioning

confidence: 99%

Gipc3 Mutation Might Cause Sensorineural Hearing Loss by Inhibiting Mitophagy in Inner Ear Hair Cells

Li,

Wang,

Shi

et al. 2024

Preprint

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Sensory hearing loss (SNHL) has a high degree of genetic heterogeneity, and there are many mutated genes that cause deafness. GIPC3 gene is one of the mutated genes that can cause congenital hearing loss found in recent years, but the mechanism of its cause is still unclear. Mitophagy is the process of selectively encapsulating and lysing damaged or dysfunctional mitochondria in order to prevent accumulation of damaged mitochondria from damaging the cells and is of great importance in the maintenance of homeostasis in the inner ear. The aim of this paper is to observe the effect of Gipc3 expression on mitochondrial metabolism and autophagy in inner ear hair cells, and to explore the possible mechanism of sensorineural hearing loss caused by Gipc3 mutations. In this study, The House Ear Institute Organ of Corti 1(HEI-OC1) cells and cochlear explants were cultured to change the expression level of Gipc3 by transfection, and the knockdown efficiency was examined by quantitative polymerase chain reaction (qPCR) and Western Blot. Knockdown of Gipc3 inhibited cell viability and its proliferation ability. When t-BHP was used to induce oxidative stress injury and knockdown of Gipc3, inner ear hair cells had weakened ability to resist oxidative stress injury, mitochondrial metabolism was altered, and there was accumulation of reactive oxygen species and reduction of mitochondrial membrane potential. Immunofluorescence and Western Blot techniques revealed that the mitochondrial autophagy-related proteins, LC3B and P62, showed autophagy disorders. A PH domain, leucine zipper motif 1(APPL1) mediates early endosome-dependent mitophagy, and deletion of APPL1 impairs mitochondrial autophagy. We found that fluorescence co-localization exists between Gipc3 and APPL1, and that they interact with each other, with positive correlation in their trends. In summary, Gipc3 mutation may lead to decreased mitochondrial function by inhibiting the APPL1-mediated mitochondrial autophagy process, out of which impaired oxidative metabolism in hair cells may occur, which is a possible mechanism for the inhibition of mitochondrial autophagy by Gipc3 mutation.

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Section: Discussionmentioning

confidence: 99%

Gipc3 Mutation Might Cause Sensorineural Hearing Loss by Inhibiting Mitophagy in Inner Ear Hair Cells

Li,

Wang,

Shi

et al. 2024

Preprint

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“…In the current study, the protein expression of GSDMD in kidney tissues was examined in the Cp-injected rats, and the results proved that the upregulation of both caspase-1 was associated with the upregulation of GSDMD renal expression. Cp-induced pyroptosis was found to play a role in both Cp-cytotoxic effects [ 71 , 72 ], as well as its associated nephrotoxicity [ 13 , 17 ], cardiotoxicity [ 73 ], and cochlear toxicity [ 74 ]. In harmony, in the current study, Cp induced a significant increase in GSDMD compared to the control group.…”

Section: Discussionmentioning

confidence: 99%

TLR4/Inflammasomes Cross-Talk and Pyroptosis Contribute to N-Acetyl Cysteine and Chlorogenic Acid Protection against Cisplatin-Induced Nephrotoxicity

et al. 2023

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Background: Cisplatin (Cp) is an antineoplastic agent with a dose-limiting nephrotoxicity. Cp-induced nephrotoxicity is characterized by the interplay of oxidative stress, inflammation, and apoptosis. Toll-4 receptors (TLR4) and NLPR3 inflammasome are pattern-recognition receptors responsible for activating inflammatory responses and are assigned to play a significant role with gasdermin (GSDMD) in acute kidney injuries. N-acetylcysteine (NAC) and chlorogenic acid (CGA) have documented nephroprotective effects by suppressing oxidative and inflammatory pathways. Therefore, the current study aimed to investigate the contribution of the upregulation of TLR4/inflammasomes/gasdermin signaling to Cp-induced nephrotoxicity and their modulation by NAC or CGA. Methods: A single injection of Cp (7 mg/kg, i.p.) was given to Wistar rats. Rats received either NAC (250 mg/kg, p.o.) and/or CGA (20 mg/kg, p.o.) one week before and after the Cp injection. Results: Cp-induced acute nephrotoxicity was evident by the increased blood urea nitrogen and serum creatinine and histopathological insults. Additionally, nephrotoxicity was associated with increased lipid peroxidation, reduced antioxidants, and elevated levels of inflammatory markers (NF-κB and TNF-α) in the kidney tissues. Moreover, Cp upregulated both TLR4/NLPR3/interleukin-1beta (IL-1β) and caspase-1/GSDMD-signaling pathways, accompanied by an increased Bax/BCL-2 ratio, indicating an inflammatory-mediated apoptosis. Both NAC and/or CGA significantly corrected these changes. Conclusions: This study emphasizes that inhibition of TLR4/NLPR3/IL-1β/GSDMD might be a novel mechanism of the nephroprotective effects of NAC or CGA against Cp-induced nephrotoxicity in rats.

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“…However, it is undesirable for the clinical application of antioxidants to alleviate the cisplatin-induced hearing loss. Cisplatin can trigger the assembly of NLRP3 inflammasome, induce marginal cell pyroptosis and cochlear damage ( Yu et al, 2022 ). The pathological morphology changes and NLRP3 expression could be suppressed by inhibiting the upstream signal TXNIP.…”

Section: 1 Nlrp3 Inflammasome Activationmentioning

confidence: 99%

Mitochondrial dysfunction in hearing loss: Oxidative stress, autophagy and NLRP3 inflammasome

Shen²,

Wang³

et al. 2023

Front. Cell Dev. Biol.

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Sensorineural deafness becomes an inevitable worldwide healthy problem, yet the current curative therapy is limited. Emerging evidences demonstrate mitochondrial dysfunction plays a vital role of in the pathogenesis of deafness. Reactive oxygen species (ROS)-induced mitochondrial dysfunction combined with NLRP3 inflammasome activation is involved in cochlear damage. Autophagy not only clears up undesired proteins and damaged mitochondria (mitophagy), but also eliminate excessive ROS. Appropriate enhancement of autophagy can reduce oxidative stress, inhibit cell apoptosis, and protect auditory cells. In addition, we further discuss the interplays linking ROS generation, NLRP3 inflammasome activation, and autophagy underlying the pathogenesis of deafness, including ototoxic drugs-, noise- and aging-related hearing loss.

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Cochlear Marginal Cell Pyroptosis Is Induced by Cisplatin via NLRP3 Inflammasome Activation

Cited by 11 publications

References 86 publications

Gipc3 Mutation Might Cause Sensorineural Hearing Loss by Inhibiting Mitophagy in Inner Ear Hair Cells

Gipc3 Mutation Might Cause Sensorineural Hearing Loss by Inhibiting Mitophagy in Inner Ear Hair Cells

TLR4/Inflammasomes Cross-Talk and Pyroptosis Contribute to N-Acetyl Cysteine and Chlorogenic Acid Protection against Cisplatin-Induced Nephrotoxicity

Mitochondrial dysfunction in hearing loss: Oxidative stress, autophagy and NLRP3 inflammasome

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