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 language | English (US) |
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Pages (from-to) | G229-G246 |
Journal | American Journal of Physiology - Gastrointestinal and Liver Physiology |
Volume | 316 |
Issue number | 2 |
DOIs | |
State | Published - Feb 2019 |
Keywords
- Claudin
- Diarrhea
- Intestinal inflammation
- Shigella flexneri
- Tight junction
ASJC Scopus subject areas
- Physiology
- Hepatology
- Gastroenterology
- Physiology (medical)