Alcohol-induced IL-17A production in Paneth cells amplifies endoplasmic reticulum stress, apoptosis, and inflammasome-IL-18 activation in the proximal small intestine in mice

B. Gyongyosi, Y. Cho, P. Lowe, C. D. Calenda, A. Iracheta-Vellve, A. Satishchandran, A. Ambade, G. Szabó

Research output: Contribution to journalArticle

Abstract

Gut microbial translocation contributes to alcoholic hepatitis. Using a mouse model of alcoholic hepatitis, we investigated the effects of chronic alcohol plus binge and found increased abundance of Paneth cells and IL-17A in the proximal small intestine (PSI). Alcohol increased IL-17A production and pro-apoptotic signaling evidenced by Bax, Bim, caspase-3, and caspase-8 increases via endoplasmic reticulum (ER) stress indicated by C/EBP homologous protein (CHOP) upregulation; this was prevented by the ER stress inhibitor, 4-PBA, in isolated crypts in vitro and in vivo. Mechanistically, IL-17 augmented alcohol-induced ER stress in isolated crypts. In vivo IL-17A blocking antibody administration in alcohol-treated mice attenuated ER stress-mediated apoptosis and IL-18 induction and prevented alcohol-induced impairment of tight junctions in the PSI and LPS translocation to the liver. Acute-on-chronic alcohol resulted in inflammasome activation, caspase-1 cleavage, and IL-18 production in the PSI. In vivo treatment with antibiotics or 4-PBA prevented CHOP upregulation and inflammasome activation. Our data suggest that alcohol upregulates innate immune mechanisms by increasing Paneth cell numbers and IL-17A release contributing to apoptosis amplification, inflammasome activation, and gut leakiness in the PSI. Binge alcohol-induced Paneth cell expansion, ER stress, and inflammasome activation in the PSI are modulated by the gut microbiome.

Original languageEnglish
JournalMucosal Immunology
DOIs
Publication statusPublished - Jan 1 2019

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Paneth Cells
Inflammasomes
Interleukin-18
Endoplasmic Reticulum Stress
Interleukin-17
Small Intestine
Alcohols
Apoptosis
Transcription Factor CHOP
Alcoholic Hepatitis
Up-Regulation
Caspase 1
Blocking Antibodies
Caspase 8
Tight Junctions
Caspase 3
Cell Count
Anti-Bacterial Agents

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Alcohol-induced IL-17A production in Paneth cells amplifies endoplasmic reticulum stress, apoptosis, and inflammasome-IL-18 activation in the proximal small intestine in mice. / Gyongyosi, B.; Cho, Y.; Lowe, P.; Calenda, C. D.; Iracheta-Vellve, A.; Satishchandran, A.; Ambade, A.; Szabó, G.

In: Mucosal Immunology, 01.01.2019.

Research output: Contribution to journalArticle

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abstract = "Gut microbial translocation contributes to alcoholic hepatitis. Using a mouse model of alcoholic hepatitis, we investigated the effects of chronic alcohol plus binge and found increased abundance of Paneth cells and IL-17A in the proximal small intestine (PSI). Alcohol increased IL-17A production and pro-apoptotic signaling evidenced by Bax, Bim, caspase-3, and caspase-8 increases via endoplasmic reticulum (ER) stress indicated by C/EBP homologous protein (CHOP) upregulation; this was prevented by the ER stress inhibitor, 4-PBA, in isolated crypts in vitro and in vivo. Mechanistically, IL-17 augmented alcohol-induced ER stress in isolated crypts. In vivo IL-17A blocking antibody administration in alcohol-treated mice attenuated ER stress-mediated apoptosis and IL-18 induction and prevented alcohol-induced impairment of tight junctions in the PSI and LPS translocation to the liver. Acute-on-chronic alcohol resulted in inflammasome activation, caspase-1 cleavage, and IL-18 production in the PSI. In vivo treatment with antibiotics or 4-PBA prevented CHOP upregulation and inflammasome activation. Our data suggest that alcohol upregulates innate immune mechanisms by increasing Paneth cell numbers and IL-17A release contributing to apoptosis amplification, inflammasome activation, and gut leakiness in the PSI. Binge alcohol-induced Paneth cell expansion, ER stress, and inflammasome activation in the PSI are modulated by the gut microbiome.",
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AU - Lowe, P.

AU - Calenda, C. D.

AU - Iracheta-Vellve, A.

AU - Satishchandran, A.

AU - Ambade, A.

AU - Szabó, G.

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