Interleukin-33 Promotes REG3γ Expression in Intestinal Epithelial Cells and Regulates Gut Microbiota

Yi Xiao, Xiangsheng Huang, Ye Zhao, Feidi Chen, Mingming Sun, Wenjing Yang, Liang Chen, Suxia Yao, Alex-Giovanny Peniche-Trujillo, Sara Dann-Grice, Jiaren Sun, George Golovko, Yuriy Fofanov, Yinglei Miao, Zhanju Liu, Daiwen Chen, Yingzi Cong

Research output: Contribution to journalArticle

Abstract

Background & Aims: Regenerating islet-derived protein (REG3γ), an antimicrobial peptide, typically expressed by intestinal epithelial cells (IEC), plays crucial roles in intestinal homeostasis and controlling gut microbiota. However, the mechanisms that regulate IEC expression of REG3γ are still largely unclear. In this study, we investigated whether and how interleukin (IL)33, an alarmin produced by IEC in response to injury, regulates REG3γ expression in IEC, thus contributing to intestinal homeostasis. Methods: IEC were isolated from wild-type and IL33 -/- mice to determine expression of REG3γ and other antimicrobial peptides by quantitative real-time polymerase chain reaction and Western blot. IEC cell lines were used for mechanistic studies. 16S rRNA pyrosequencing analysis was used for measuring gut microbiota. Citrobacter rodentium was used for enteric infections. Results: The expression of REG3γ, but not β-defensins, in IECs of IL33 -/- mice was significantly lower than wild-type mice. IL33 treatment induced IEC expression of REG3γ in both mice and human cell lines. Mechanistically, IL33 activated STAT3, mTOR, and ERK1/2 in IEC. Inhibition of these pathways abrogated IL33-induction of REG3γ. IL33 -/- mice demonstrated higher bacteria loads and altered microbiota composition. IL33 did not directly inhibit bacterial growth, but promoted wild-type, not REG3γKO, IECs to kill bacteria in vitro. Consistently, C rodentium infection induced IEC IL33 expression, and IL33 -/- mice demonstrated an impaired bacterial clearance with C rodentium infection. Conclusions: Our study demonstrated that IL33, which is produced by IEC in response to injury and inflammatory stimulation, in turn promotes IEC expression of REG3γ, and controls the gut microbiota of the host.

Original languageEnglish (US)
Pages (from-to)21-36
Number of pages16
JournalCMGH
Volume8
Issue number1
DOIs
StatePublished - Jan 1 2019

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Epithelial Cells
Citrobacter rodentium
Homeostasis
Gastrointestinal Microbiome
Interleukin-33
Infection
Bacteria
Defensins
Cell Line
Peptides
Microbiota
Wounds and Injuries
Real-Time Polymerase Chain Reaction
Western Blotting
Growth

Keywords

  • IEC
  • IL33
  • Microbiota
  • REG3γ

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Interleukin-33 Promotes REG3γ Expression in Intestinal Epithelial Cells and Regulates Gut Microbiota. / Xiao, Yi; Huang, Xiangsheng; Zhao, Ye; Chen, Feidi; Sun, Mingming; Yang, Wenjing; Chen, Liang; Yao, Suxia; Peniche-Trujillo, Alex-Giovanny; Dann-Grice, Sara; Sun, Jiaren; Golovko, George; Fofanov, Yuriy; Miao, Yinglei; Liu, Zhanju; Chen, Daiwen; Cong, Yingzi.

In: CMGH, Vol. 8, No. 1, 01.01.2019, p. 21-36.

Research output: Contribution to journalArticle

Xiao, Yi ; Huang, Xiangsheng ; Zhao, Ye ; Chen, Feidi ; Sun, Mingming ; Yang, Wenjing ; Chen, Liang ; Yao, Suxia ; Peniche-Trujillo, Alex-Giovanny ; Dann-Grice, Sara ; Sun, Jiaren ; Golovko, George ; Fofanov, Yuriy ; Miao, Yinglei ; Liu, Zhanju ; Chen, Daiwen ; Cong, Yingzi. / Interleukin-33 Promotes REG3γ Expression in Intestinal Epithelial Cells and Regulates Gut Microbiota. In: CMGH. 2019 ; Vol. 8, No. 1. pp. 21-36.
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abstract = "Background & Aims: Regenerating islet-derived protein (REG3γ), an antimicrobial peptide, typically expressed by intestinal epithelial cells (IEC), plays crucial roles in intestinal homeostasis and controlling gut microbiota. However, the mechanisms that regulate IEC expression of REG3γ are still largely unclear. In this study, we investigated whether and how interleukin (IL)33, an alarmin produced by IEC in response to injury, regulates REG3γ expression in IEC, thus contributing to intestinal homeostasis. Methods: IEC were isolated from wild-type and IL33 -/- mice to determine expression of REG3γ and other antimicrobial peptides by quantitative real-time polymerase chain reaction and Western blot. IEC cell lines were used for mechanistic studies. 16S rRNA pyrosequencing analysis was used for measuring gut microbiota. Citrobacter rodentium was used for enteric infections. Results: The expression of REG3γ, but not β-defensins, in IECs of IL33 -/- mice was significantly lower than wild-type mice. IL33 treatment induced IEC expression of REG3γ in both mice and human cell lines. Mechanistically, IL33 activated STAT3, mTOR, and ERK1/2 in IEC. Inhibition of these pathways abrogated IL33-induction of REG3γ. IL33 -/- mice demonstrated higher bacteria loads and altered microbiota composition. IL33 did not directly inhibit bacterial growth, but promoted wild-type, not REG3γKO, IECs to kill bacteria in vitro. Consistently, C rodentium infection induced IEC IL33 expression, and IL33 -/- mice demonstrated an impaired bacterial clearance with C rodentium infection. Conclusions: Our study demonstrated that IL33, which is produced by IEC in response to injury and inflammatory stimulation, in turn promotes IEC expression of REG3γ, and controls the gut microbiota of the host.",
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T1 - Interleukin-33 Promotes REG3γ Expression in Intestinal Epithelial Cells and Regulates Gut Microbiota

AU - Xiao, Yi

AU - Huang, Xiangsheng

AU - Zhao, Ye

AU - Chen, Feidi

AU - Sun, Mingming

AU - Yang, Wenjing

AU - Chen, Liang

AU - Yao, Suxia

AU - Peniche-Trujillo, Alex-Giovanny

AU - Dann-Grice, Sara

AU - Sun, Jiaren

AU - Golovko, George

AU - Fofanov, Yuriy

AU - Miao, Yinglei

AU - Liu, Zhanju

AU - Chen, Daiwen

AU - Cong, Yingzi

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N2 - Background & Aims: Regenerating islet-derived protein (REG3γ), an antimicrobial peptide, typically expressed by intestinal epithelial cells (IEC), plays crucial roles in intestinal homeostasis and controlling gut microbiota. However, the mechanisms that regulate IEC expression of REG3γ are still largely unclear. In this study, we investigated whether and how interleukin (IL)33, an alarmin produced by IEC in response to injury, regulates REG3γ expression in IEC, thus contributing to intestinal homeostasis. Methods: IEC were isolated from wild-type and IL33 -/- mice to determine expression of REG3γ and other antimicrobial peptides by quantitative real-time polymerase chain reaction and Western blot. IEC cell lines were used for mechanistic studies. 16S rRNA pyrosequencing analysis was used for measuring gut microbiota. Citrobacter rodentium was used for enteric infections. Results: The expression of REG3γ, but not β-defensins, in IECs of IL33 -/- mice was significantly lower than wild-type mice. IL33 treatment induced IEC expression of REG3γ in both mice and human cell lines. Mechanistically, IL33 activated STAT3, mTOR, and ERK1/2 in IEC. Inhibition of these pathways abrogated IL33-induction of REG3γ. IL33 -/- mice demonstrated higher bacteria loads and altered microbiota composition. IL33 did not directly inhibit bacterial growth, but promoted wild-type, not REG3γKO, IECs to kill bacteria in vitro. Consistently, C rodentium infection induced IEC IL33 expression, and IL33 -/- mice demonstrated an impaired bacterial clearance with C rodentium infection. Conclusions: Our study demonstrated that IL33, which is produced by IEC in response to injury and inflammatory stimulation, in turn promotes IEC expression of REG3γ, and controls the gut microbiota of the host.

AB - Background & Aims: Regenerating islet-derived protein (REG3γ), an antimicrobial peptide, typically expressed by intestinal epithelial cells (IEC), plays crucial roles in intestinal homeostasis and controlling gut microbiota. However, the mechanisms that regulate IEC expression of REG3γ are still largely unclear. In this study, we investigated whether and how interleukin (IL)33, an alarmin produced by IEC in response to injury, regulates REG3γ expression in IEC, thus contributing to intestinal homeostasis. Methods: IEC were isolated from wild-type and IL33 -/- mice to determine expression of REG3γ and other antimicrobial peptides by quantitative real-time polymerase chain reaction and Western blot. IEC cell lines were used for mechanistic studies. 16S rRNA pyrosequencing analysis was used for measuring gut microbiota. Citrobacter rodentium was used for enteric infections. Results: The expression of REG3γ, but not β-defensins, in IECs of IL33 -/- mice was significantly lower than wild-type mice. IL33 treatment induced IEC expression of REG3γ in both mice and human cell lines. Mechanistically, IL33 activated STAT3, mTOR, and ERK1/2 in IEC. Inhibition of these pathways abrogated IL33-induction of REG3γ. IL33 -/- mice demonstrated higher bacteria loads and altered microbiota composition. IL33 did not directly inhibit bacterial growth, but promoted wild-type, not REG3γKO, IECs to kill bacteria in vitro. Consistently, C rodentium infection induced IEC IL33 expression, and IL33 -/- mice demonstrated an impaired bacterial clearance with C rodentium infection. Conclusions: Our study demonstrated that IL33, which is produced by IEC in response to injury and inflammatory stimulation, in turn promotes IEC expression of REG3γ, and controls the gut microbiota of the host.

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