Inhibition of HSP90 and Activation of HSF1 Diminish Macrophage NLRP3 Inflammasome Activity in Alcohol-Associated Liver Injury.
Adult
Aged
Animals
Benzoquinones
/ pharmacology
Caspase 1
/ drug effects
Cytokines
/ metabolism
Disease Models, Animal
Female
HSP90 Heat-Shock Proteins
/ antagonists & inhibitors
Heat Shock Transcription Factors
/ metabolism
Humans
In Vitro Techniques
Interleukin-18
/ metabolism
Interleukin-1beta
/ metabolism
Lactams, Macrocyclic
/ pharmacology
Liver Cirrhosis, Alcoholic
/ genetics
Liver Diseases, Alcoholic
/ genetics
Macrophages
/ drug effects
Male
Mice
Middle Aged
NLR Family, Pyrin Domain-Containing 3 Protein
/ genetics
Neoplasm Proteins
RNA, Messenger
/ metabolism
Young Adult
17-DMAG
Caspase-1
Gasdermin D
HSPA1A
alcohol-associated liver disease
Journal
Alcoholism, clinical and experimental research
ISSN: 1530-0277
Titre abrégé: Alcohol Clin Exp Res
Pays: England
ID NLM: 7707242
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
23
12
2019
accepted:
31
03
2020
pubmed:
14
4
2020
medline:
15
12
2021
entrez:
14
4
2020
Statut:
ppublish
Résumé
Activation of NLRP3 in liver macrophages contributes to alcohol-associated liver disease (ALD). Molecular chaperone heat shock protein (HSP) 90 facilitates NLRP3 inflammasome activity during infections and inflammatory diseases. We previously reported that HSP90 is induced in ALD and regulates proinflammatory cytokines, tumor necrosis factor alpha, and IL-6. Whether HSP90 affects IL-1β and IL-18 regulated by NLRP3 inflammasome in ALD is unknown. Here, we hypothesize that HSP90 modulated NLRP3 inflammasome activity and affects IL-1β and IL-18 secretion in ALD. The expression of HSP90AA1 and NLRP3 inflammasome genes was evaluated in human alcoholic livers and in mouse model of ALD. The importance of HSP90 on NLRP3 inflammasome activation in ALD was evaluated by administering HSP90 inhibitor, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) to mice subjected to ALD, and in vitro to bone marrow-derived macrophages (BMDM) stimulated with LPS and ATP. The effect of activation of HSF1/HSPA1A axis during HSP90 inhibition or direct activation during heat shock of BMDMs on NLRP3 activity and secretion of downstream cytokines was evaluated. We found positive correlation between induction of HSP90 and NLRP3 inflammasome genes in human alcoholic cirrhotic livers. Administration of 17-DMAG in mouse model of ALD significantly down-regulated NLRP3 inflammasome-mediated caspase-1 (CASP-1) activity and cytokine secretion, with reduction in ALD. 17-DMAG-mediated decrease in NLRP3 was restricted to liver macrophages. Using BMDMs, we show that inhibition of HSP90 prevented CASP-1 activity, and Gasdermin D (GSDMD) cleavage, important in release of active IL-1β and IL-18. Interestingly, activation of the heat shock factor 1 (HSF1)/HSPA1A axis, either during HSP90 inhibition or by heat shock, decreased NLRP3 inflammasome activity and reduced secretion of cytokines. Our studies indicate that inhibition of HSP90 and activation of HSF1/HSPA1A reduce IL-1β and IL-18 via decrease in NLRP3/CASP-1 and GSDMD activity in ALD.
Sections du résumé
BACKGROUND
Activation of NLRP3 in liver macrophages contributes to alcohol-associated liver disease (ALD). Molecular chaperone heat shock protein (HSP) 90 facilitates NLRP3 inflammasome activity during infections and inflammatory diseases. We previously reported that HSP90 is induced in ALD and regulates proinflammatory cytokines, tumor necrosis factor alpha, and IL-6. Whether HSP90 affects IL-1β and IL-18 regulated by NLRP3 inflammasome in ALD is unknown. Here, we hypothesize that HSP90 modulated NLRP3 inflammasome activity and affects IL-1β and IL-18 secretion in ALD.
METHODS
The expression of HSP90AA1 and NLRP3 inflammasome genes was evaluated in human alcoholic livers and in mouse model of ALD. The importance of HSP90 on NLRP3 inflammasome activation in ALD was evaluated by administering HSP90 inhibitor, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) to mice subjected to ALD, and in vitro to bone marrow-derived macrophages (BMDM) stimulated with LPS and ATP. The effect of activation of HSF1/HSPA1A axis during HSP90 inhibition or direct activation during heat shock of BMDMs on NLRP3 activity and secretion of downstream cytokines was evaluated.
RESULTS
We found positive correlation between induction of HSP90 and NLRP3 inflammasome genes in human alcoholic cirrhotic livers. Administration of 17-DMAG in mouse model of ALD significantly down-regulated NLRP3 inflammasome-mediated caspase-1 (CASP-1) activity and cytokine secretion, with reduction in ALD. 17-DMAG-mediated decrease in NLRP3 was restricted to liver macrophages. Using BMDMs, we show that inhibition of HSP90 prevented CASP-1 activity, and Gasdermin D (GSDMD) cleavage, important in release of active IL-1β and IL-18. Interestingly, activation of the heat shock factor 1 (HSF1)/HSPA1A axis, either during HSP90 inhibition or by heat shock, decreased NLRP3 inflammasome activity and reduced secretion of cytokines.
CONCLUSION
Our studies indicate that inhibition of HSP90 and activation of HSF1/HSPA1A reduce IL-1β and IL-18 via decrease in NLRP3/CASP-1 and GSDMD activity in ALD.
Identifiants
pubmed: 32282939
doi: 10.1111/acer.14338
pmc: PMC7328660
mid: NIHMS1591517
doi:
Substances chimiques
Benzoquinones
0
Cytokines
0
Gsdma protein, mouse
0
HSF1 protein, human
0
HSP90 Heat-Shock Proteins
0
HSP90AA1 protein, human
0
Heat Shock Transcription Factors
0
Hsf1 protein, mouse
0
IL1B protein, mouse
0
Interleukin-18
0
Interleukin-1beta
0
Lactams, Macrocyclic
0
NLR Family, Pyrin Domain-Containing 3 Protein
0
NLRP3 protein, human
0
Neoplasm Proteins
0
Nlrp3 protein, mouse
0
RNA, Messenger
0
17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
001L2FE0M3
Caspase 1
EC 3.4.22.36
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1300-1311Subventions
Organisme : NIAAA NIH HHS
ID : R01 AA017986
Pays : United States
Organisme : NIAAA NIH HHS
ID : R01 AA025289
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI146855
Pays : United States
Organisme : National Institute of Alcohol Abuse and Alcoholism
ID : R01 AA25289-01
Pays : International
Informations de copyright
© 2020 by the Research Society on Alcoholism.
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