Inhibition of HSP90 and Activation of HSF1 Diminish Macrophage NLRP3 Inflammasome Activity in Alcohol‐Associated Liver Injury

Choudhury, Asmita; Bullock, Daniel; Lim, Arlene; Argemí, Josepmaria; Orning, Pontus; Lien, Egil; Bataller, Ramón; Mandrekar, Pranoti

doi:10.1111/acer.14338

Cited by 39 publications

(23 citation statements)

References 32 publications

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“…Previous studies using natural product-derived HSP90 inhibitors, such as carnosol, geldanamycin or its analogue 17-DMAG, have suggested that HSP90 modulates inflammation partly via NLRP3 inhibition. 14,18,19 As well-characterized synthetic HSP90 inhibitors, some of which are in clinical trials, are commercially available, we decided to test a number of structurally distinct HSP90 inhibitors in NLRP3 inflammasome assays. Initially, we used an NLRP3 inflammasome assay based on the formation of ASC specks in an ASC-mCherry-expressing mouse iBMDM cell line.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of the NLRP3 inflammasome by HSP90 inhibitors

et al. 2020

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Summary Excessive and dysregulated inflammation is known to contribute to disease progression. HSP90 is an intracellular chaperone known to regulate inflammatory processes including the NLRP3 inflammasome and secretion of the pro‐inflammatory cytokine interleukin(IL)‐1β. Here, primarily using an in vitro inflammasome ASC speck assay, and an in vivo model of murine peritonitis, we tested the utility of HSP90 inhibitors as anti‐inflammatory molecules. We report that the HSP90 inhibitor EC144 effectively inhibited inflammatory processes including priming and activation of NLRP3 in vitro and in vivo . A specific inhibitor of the β HSP90 isoform was ineffective suggesting the importance of the α isoform in inflammatory signalling. EC144 inhibited IL‐1β and IL‐6 in vivo when administered orally, and was brain‐penetrant. These data suggest that HSP90 inhibitors may be useful for targeting inflammation in diverse diseases that are worsened by the presence of inflammation.

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Section: Resultsmentioning

confidence: 99%

Inhibition of the NLRP3 inflammasome by HSP90 inhibitors

et al. 2020

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“…However, despite of signi cantly increased circulating TNF-α, hepatic expression of HSP72 decreased in presence of heat stress combined with PM 2.5 exposure. Studies have shown that excessive expression of in ammatory factor TNF-α could inhibit the HSF1/HSPA1A axis, which is critical for the transcription of HSP72 [36,37]. Thus, protective upregulation of HSP72 induced by heat could be offset by PM 2.5 exposure plus heat stress-enhanced TNF-α secretion.…”

Section: Discussionmentioning

confidence: 99%

Joint Effects of Heat Stress and PM2.5 Exposure on Glucose Metabolism and Hepatic Insulin Signaling

Gu¹,

Cai²,

Zhong³

et al. 2021

Preprint

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Background: Heatwave events are occurring more frequently, accompanied by a significant increase in the ambient concentration of fine particulate matter (PM2.5). Epidemiological studies have suggested that heat stress or PM2.5 exposure would impair glucose homeostasis and insulin sensitivity, but the combined effect and the exact mechanisms are not well understood.Methods: C57BL/6 mice were randomly divided into filtered air (FA), fine particulate matter (PM) group, filtered air combined with heat stress (FH) group, and fine particulate matter combined with heat stress (PH) group for a 4-week PM2.5 exposure, followed by a 2-week heat stress exposure, via a whole-body exposure system. Systemic glucose homeostasis, insulin sensitivity, and circulating inflammatory cytokines were examined. HSP72 expression and insulin signaling in the liver were measured.Results: Glucose tolerance and insulin sensitivity were impaired in response to heat stress, accompanied by lessened hepatic GLUT2 expression and inhibited insulin signaling pathway. No synergistic effects of heat stress and PM2.5 exposure on glucose homeostasis were observed, while heat-upregulated HSP72 expression was attenuated with accumulated TNF-α induced by further PM2.5 exposure.Conclusions: Heat stress combined with PM2.5 exposure induced TNF-α, which could inhibit heat-elevated hepatic HSP72 expression. Elevated circulating TNF-α impaired hepatic insulin signaling and GLUT2 expression. Then, glucose homeostasis was perturbed, and insulin action was impaired.

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“…Pyroptosis, which is also known as cellular inflammatory necrosis, induces the release of cellular contents to activate the inflammatory response 22 . Previous studies demonstrated that the high expression of Caspase‐1 and GSDMD was an indicator of pyroptosis 23,24 . The inhibition caused by small molecule is more efficient than single blockade of other components (ASC, Caspase‐1) or its downstream IL‐1β, suggesting that NLRP3 is a central molecule in the NLRP3‐Caspase‐1‐IL1β pathway 25 .…”

Section: Discussionmentioning

confidence: 99%

Protective effect of Aster tataricus extract on NLRP3‐mediated pyroptosis of bladder urothelial cells

Wang

Yin

Zhou

et al. 2020

J Cellular Molecular Medi

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Aster tataricus L.f. is a traditional Eastern Asian herbal medicine used for the relief of uroschesis‐related illnesses and has been demonstrated clinically to exert satisfied effects. However, the mechanism of its therapeutic action remains unclear. The present study aimed to evaluate the protective mechanism of Aster tataricus extract (ATE) on CYP or LPS + ATP‐induced interstitial cystitis (IC), we successfully constructed the induced IC Sprague‐Dawley (SD) rat model and IC human urothelium cell (SV‐HUC‐1) model. The main compounds of ATE were determined by LC‐MS. After intervention, the changes on the bladder wall morphology and inflammation were observed in each group. SV‐HUC1 cell viability was measured by MTT and double stained with Hoechst 33342 and propidium iodide (PI). The expression levels of NLRP3, Pro‐caspase‐1, Caspsae‐1 p20, GSDMD, GSDMD‐N and Cleave‐IL‐1β in vivo and in vitro in different groups were detected by Western blotting. ATE significantly alleviated oedema and haemorrhage and reduced the inflammation index and histopathological score in SD rat bladder. The results of cell revealed that ATE could improve cell viability and decrease pyroptosis ratio. The expression of NLRP3 and other pyroptosis‐related protein was remarkably decreased by ATE both in vivo and in vitro. ATE may be used as an inhibitor of NLRP3 in treating IC. The discovery of NLRP3/Caspase‐1/GSDMD‐N as a new protective pathway provides a new direction for protecting cell against IC.

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Inhibition of HSP90 and Activation of HSF1 Diminish Macrophage NLRP3 Inflammasome Activity in Alcohol‐Associated Liver Injury

Cited by 39 publications

References 32 publications

Inhibition of the NLRP3 inflammasome by HSP90 inhibitors

Inhibition of the NLRP3 inflammasome by HSP90 inhibitors

Joint Effects of Heat Stress and PM2.5 Exposure on Glucose Metabolism and Hepatic Insulin Signaling

Protective effect of Aster tataricus extract on NLRP3‐mediated pyroptosis of bladder urothelial cells

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