Research Article: Colonic levels of vasoactive intestinal peptide decrease during infection and exogenous VIP protects epithelial mitochondria against the negative effects of IFNγ and TNFα induced during Citrobacter rodentium infection

Date Published: September 25, 2018

Publisher: Public Library of Science

Author(s): Arpan K. Maiti, Sinan Sharba, Nazanin Navabi, Sara K. Lindén, Shahid Umar.

http://doi.org/10.1371/journal.pone.0204567

Abstract

Citrobacter rodentium infection is a model for infection with attaching and effacing pathogens, such as enteropathogenic Escherichia coli. The vasoactive intestinal peptide (VIP) has emerged as an anti-inflammatory agent, documented to inhibit Th1 immune responses and successfully treat animal models of inflammation. VIP is also a mucus secretagogue. Here, we found that colonic levels of VIP decrease during murine C. rodentium infection with a similar time dependency as measurements reflecting mitochondrial function and epithelial integrity. The decrease in VIP appears mainly driven by changes in the cytokine environment, as no changes in VIP levels were detected in infected mice lacking interferon gamma (IFNγ). VIP supplementation alleviated the reduction of activity and levels of mitochondrial respiratory complexes I and IV, mitochondrial phosphorylation capacity, transmembrane potential and ATP generation caused by IFNγ, TNFα and C. rodentium infection, in an in vitro mucosal surface. Similarly, VIP treatment regimens that included the day 5–10 post infection period alleviated decreases in enzyme complexes I and IV, phosphorylation capacity, mitochondrial transmembrane potential and ATP generation as well as increased apoptosis levels during murine infection with C. rodentium. However, VIP treatment failed to alleviate colitis, although there was a tendency to decreased pathogen density in contact with the epithelium and in the spleen. Both in vivo and in vitro, NO generation increased during C. rodentium infection, which was alleviated by VIP. Thus, therapeutic VIP administration to restore the decreased levels during infection had beneficial effects on epithelial cells and their mitochondria, but not on the overall infection outcome.

Partial Text

Murine Citrobacter rodentium infection models infection with human enterohemorrhagic (EHEC) and enteropathogenic Escherichia coli (EPEC) [1–3]. Infection induces colitis with a mild transmural inflammatory infiltrate, colonic epithelial damage, goblet cell depletion and colonic crypt hyperplasia [4–6]. Concomitantly, colonic epithelial cell death is also observed, both at the luminal surface and base of the crypts [1, 7–9]. The attaching and effacing (A/E) pathogen C. rodentium mainly infects the luminal epithelial cells through the formation of a type III secretion system (T3SS), which initiates the host cell death pathway by inducing effector molecules like EspF and Map that translocate into the host mitochondria disrupting mitochondrial function [10–13]. In addition, enhanced levels of pro-inflammatory cytokines induce mitochondrial dysfunction [14], which contributes to colonic epithelial cell death during infection. From the observed Th1 response, mainly upregulation of interferon gamma (IFNγ) and tumor necrosis factor alpha (TNFα) occurring during the mid and late infection phases, led to severe mitochondrial dysfunction involving loss of complex-I and IV quantity and activity accompanied by a reduction in mitochondrial phosphorylation capacity, membrane potential and mitochondrial ATP generation [14].

This study demonstrated that VIP decreased during murine C. rodentium infection in a cytokine dependent manner and that VIP supplementation alleviated the reduction of activity and levels of mitochondrial respiratory complexes I and IV, mitochondrial phosphorylation capacity, transmembrane potential and ATP generation caused by IFNγ, TNFα and C. rodentium infection in an in vitro mucosal surface. Similarly, VIP treatment regimens that included the day 5–10 post infection period alleviated decreases in enzyme complexes I and IV, phosphorylation capacity, mitochondrial transmembrane potential and ATP generation as well as increased apoptosis levels during murine infection with C. rodentium, demonstrate that the timing of the treatment is vital. However, although there was a tendency to decreased pathogen density in contact with the epithelium and in the spleen, VIP treatment failed to alleviate colitis. The protective actions of VIP on mitochondria and epithelial cells is likely due to decreased oxidative damage, as the C. rodentium infection induced NO was alleviated by VIP both in vivo and in vitro. Thus, therapeutic VIP administration to restore the decreased levels during infection had beneficial effects on epithelial cells and their mitochondria, but not on the overall infection outcome.

 

Source:

http://doi.org/10.1371/journal.pone.0204567

 

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