Zinc ameliorates intestinal barrier dysfunctions in shigellosis by reinstating claudin-2 and -4 on the membranes

Paramita Sarkar, Tultul Saha, Irshad Ali Sheikh, Subhra Chakraborty, Joydeep Aoun, Manoj Kumar Chakrabarti, Vazhaikkurichi M. Rajendran, Nadia A. Ameen, Shanta Dutta, Kazi Mirajul Hoque

Research output: Contribution to journalArticle

Abstract

Whether zinc (Zn2+) regulates barrier functions by modulating tight-junction (TJ) proteins when pathogens such as Shigella alter epithelial permeability is still unresolved. We investigated the potential benefits of Zn2+ in restoring impaired barrier function in vivo in Shigella-infected mouse tissue and in vitro in T84 cell monolayers. Basolateral Shigella infection triggered a time-dependent decrease in transepithelial resistance followed by an increase in paracellular permeability of FITC-labeled dextran and altered ion selectivity. This led to ion and water loss into the intestinal lumen. Immunofluorescence studies revealed redistribution of claudin-2 and -4 to an intracellular location and accumulation of these proteins in the cytoplasm following infection. Zn2+ ameliorated this perturbed barrier by redistribution of claudin-2 and -4 back to the plasma membrane and by modulating the phosphorylation state of TJ proteins t hough extracellular signal-regulated kinase (ERK)1/2 dependency. Zn2+ prevents elevation of IL-6 and IL-8. Mice challenged with Shigella showed that oral Zn2+supplementation diminished diverse pathophysiological symptoms of shigellosis. Claudin-2 and -4 were susceptible to Shigella infection, resulting in altered barrier function and increased levels of IL-6 and IL-8. Zn2+ supplementation ameliorated this barrier dysfunction, and the inflammatory response involving ERK-mediated change of phosphorylation status for claudin-2 and -4. Thus, Zn2+ may have potential therapeutic value in inflammatory diarrhea and shigellosis. NEW & NOTEWORTHY Our study addresses whether Zn2+ could be an alternative strategy to reduce Shigella-induced inflammatory response and epithelial barrier dysfunction. We have defined a mechanism in terms of intracellular signaling pathways and tight-junction protein expression by Zn2+. Claudin-2 and -4 are susceptible to Shigella infection, whereas in the presence of Zn2+ they are resistant to infection-related barrier dysfunction involving ERK-mediated change of phosphorylation status of claudins.

Original languageEnglish (US)
Pages (from-to)G229-G246
JournalAmerican journal of physiology. Gastrointestinal and liver physiology
Volume316
Issue number2
DOIs
StatePublished - Feb 1 2019

Fingerprint

Claudin-2
Claudin-4
Bacillary Dysentery
Shigella
Zinc
Membranes
Tight Junction Proteins
Infection
Extracellular Signal-Regulated MAP Kinases
Phosphorylation
Interleukin-8
Permeability
Interleukin-6
Claudins
Ions
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Fluorescent Antibody Technique
Diarrhea
Cytoplasm

Keywords

  • intestinal inflammation
  • claudin
  • diarrhea
  • tight junction

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

Cite this

Zinc ameliorates intestinal barrier dysfunctions in shigellosis by reinstating claudin-2 and -4 on the membranes. / Sarkar, Paramita; Saha, Tultul; Sheikh, Irshad Ali; Chakraborty, Subhra; Aoun, Joydeep; Chakrabarti, Manoj Kumar; Rajendran, Vazhaikkurichi M.; Ameen, Nadia A.; Dutta, Shanta; Hoque, Kazi Mirajul.

In: American journal of physiology. Gastrointestinal and liver physiology, Vol. 316, No. 2, 01.02.2019, p. G229-G246.

Research output: Contribution to journalArticle

Sarkar, Paramita ; Saha, Tultul ; Sheikh, Irshad Ali ; Chakraborty, Subhra ; Aoun, Joydeep ; Chakrabarti, Manoj Kumar ; Rajendran, Vazhaikkurichi M. ; Ameen, Nadia A. ; Dutta, Shanta ; Hoque, Kazi Mirajul. / Zinc ameliorates intestinal barrier dysfunctions in shigellosis by reinstating claudin-2 and -4 on the membranes. In: American journal of physiology. Gastrointestinal and liver physiology. 2019 ; Vol. 316, No. 2. pp. G229-G246.
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AU - Aoun, Joydeep

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AU - Rajendran, Vazhaikkurichi M.

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