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The role of peroxisome proliferator-activated receptor γ in immune responses to enteroaggregative Escherichia coli infection.

Philipson CW, Bassaganya-Riera J, Viladomiu M, Pedragosa M, Guerrant RL, Roche JK, Hontecillas R - PLoS ONE (2013)

Bottom Line: At the molecular level, both pharmacological blockade and deletion of PPARγ in T cells resulted in upregulation of TGF-β, IL-6, IL-17 and anti-microbial peptides, enhanced Th17 responses, fewer colonic lesions, faster clearance of EAEC, and improved recovery.The beneficial effects of PPARγ blockade on weight loss and EAEC clearance were abrogated by neutralizing IL-17 in vivo.Our studies provide in vivo evidence supporting the beneficial role of mucosal innate and effector T cell responses on EAEC burden and suggest pharmacological blockade of PPARγ as a novel therapeutic intervention for EAEC infection.

View Article: PubMed Central - PubMed

Affiliation: Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America.

ABSTRACT

Background: Enteroaggregative Escherichia coli (EAEC) is recognized as an emerging cause of persistent diarrhea and enteric disease worldwide. Mucosal immunity towards EAEC infections is incompletely understood due in part to the lack of appropriate animal models. This study presents a new mouse model and investigates the role of peroxisome proliferator-activated receptor gamma (PPARγ) in the modulation of host responses to EAEC in nourished and malnourished mice.

Methods/principal findings: Wild-type and T cell-specific PPARγ C57BL/6 mice were fed protein-deficient diets at weaning and challenged with 5×10(9)cfu EAEC strain JM221 to measure colonic gene expression and immune responses to EAEC. Antigen-specific responses to E. coli antigens were measured in nourished and malnourished mice following infection and demonstrated the immunosuppressive effects of malnutrition at the cellular level. At the molecular level, both pharmacological blockade and deletion of PPARγ in T cells resulted in upregulation of TGF-β, IL-6, IL-17 and anti-microbial peptides, enhanced Th17 responses, fewer colonic lesions, faster clearance of EAEC, and improved recovery. The beneficial effects of PPARγ blockade on weight loss and EAEC clearance were abrogated by neutralizing IL-17 in vivo.

Conclusions: Our studies provide in vivo evidence supporting the beneficial role of mucosal innate and effector T cell responses on EAEC burden and suggest pharmacological blockade of PPARγ as a novel therapeutic intervention for EAEC infection.

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Early beneficial effects of PPARγ deficiency in T cells during enteroaggregative Escherichia coli (EAEC) challenge.Growth retardation in wild type (A) and T cell specific PPARγ deficient mice (B) is expressed as percent growth from day 0 after challenge. Gene expression for IL-6 and TNF-α in colonic tissue of malnourished C57BL/6 and PPARγ CD4cre+ mice was analyzed using quantitative real-time RT-PCR on day 5 PI (C). Representative photomicrographs of colonic specimens of infected mice at 5 or 14 days PI in infected wild type mice (D,E,I,J), infected mice lacking PPARγ expression in T cells (F,G,K,L), and uninfected controls (H,M). The top panel corresponds to nourished mice whereas the bottom panel corresponds to malnourished mice. Original magnification 200×. Boxes and arrows are areas where an amplified image (400×) is provided to emphasize examples of leukocyte infiltration, mucosal thickening, goblet cell hyperplasia, and vasodilation. Mice per group: n = 8. Asterisks indicate values where differences are statistically significant (p<0.05).
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pone-0057812-g001: Early beneficial effects of PPARγ deficiency in T cells during enteroaggregative Escherichia coli (EAEC) challenge.Growth retardation in wild type (A) and T cell specific PPARγ deficient mice (B) is expressed as percent growth from day 0 after challenge. Gene expression for IL-6 and TNF-α in colonic tissue of malnourished C57BL/6 and PPARγ CD4cre+ mice was analyzed using quantitative real-time RT-PCR on day 5 PI (C). Representative photomicrographs of colonic specimens of infected mice at 5 or 14 days PI in infected wild type mice (D,E,I,J), infected mice lacking PPARγ expression in T cells (F,G,K,L), and uninfected controls (H,M). The top panel corresponds to nourished mice whereas the bottom panel corresponds to malnourished mice. Original magnification 200×. Boxes and arrows are areas where an amplified image (400×) is provided to emphasize examples of leukocyte infiltration, mucosal thickening, goblet cell hyperplasia, and vasodilation. Mice per group: n = 8. Asterisks indicate values where differences are statistically significant (p<0.05).

Mentions: Detrimental growth shortfalls were observed in infected malnourished mice of all genotypes as early as day three post-infection (PI). Malnourished mice never gained more than 15% of their body weight due to severe protein deficiency. PPARγ CD4cre+ mice on a control diet grew at rates similar to uninfected mice while nourished infected wild type (WT) mice experienced significant retardation in growth up to 11 days after challenge (Figure 1A–B).


The role of peroxisome proliferator-activated receptor γ in immune responses to enteroaggregative Escherichia coli infection.

Philipson CW, Bassaganya-Riera J, Viladomiu M, Pedragosa M, Guerrant RL, Roche JK, Hontecillas R - PLoS ONE (2013)

Early beneficial effects of PPARγ deficiency in T cells during enteroaggregative Escherichia coli (EAEC) challenge.Growth retardation in wild type (A) and T cell specific PPARγ deficient mice (B) is expressed as percent growth from day 0 after challenge. Gene expression for IL-6 and TNF-α in colonic tissue of malnourished C57BL/6 and PPARγ CD4cre+ mice was analyzed using quantitative real-time RT-PCR on day 5 PI (C). Representative photomicrographs of colonic specimens of infected mice at 5 or 14 days PI in infected wild type mice (D,E,I,J), infected mice lacking PPARγ expression in T cells (F,G,K,L), and uninfected controls (H,M). The top panel corresponds to nourished mice whereas the bottom panel corresponds to malnourished mice. Original magnification 200×. Boxes and arrows are areas where an amplified image (400×) is provided to emphasize examples of leukocyte infiltration, mucosal thickening, goblet cell hyperplasia, and vasodilation. Mice per group: n = 8. Asterisks indicate values where differences are statistically significant (p<0.05).
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getmorefigures.php?uid=PMC3585146&req=5

pone-0057812-g001: Early beneficial effects of PPARγ deficiency in T cells during enteroaggregative Escherichia coli (EAEC) challenge.Growth retardation in wild type (A) and T cell specific PPARγ deficient mice (B) is expressed as percent growth from day 0 after challenge. Gene expression for IL-6 and TNF-α in colonic tissue of malnourished C57BL/6 and PPARγ CD4cre+ mice was analyzed using quantitative real-time RT-PCR on day 5 PI (C). Representative photomicrographs of colonic specimens of infected mice at 5 or 14 days PI in infected wild type mice (D,E,I,J), infected mice lacking PPARγ expression in T cells (F,G,K,L), and uninfected controls (H,M). The top panel corresponds to nourished mice whereas the bottom panel corresponds to malnourished mice. Original magnification 200×. Boxes and arrows are areas where an amplified image (400×) is provided to emphasize examples of leukocyte infiltration, mucosal thickening, goblet cell hyperplasia, and vasodilation. Mice per group: n = 8. Asterisks indicate values where differences are statistically significant (p<0.05).
Mentions: Detrimental growth shortfalls were observed in infected malnourished mice of all genotypes as early as day three post-infection (PI). Malnourished mice never gained more than 15% of their body weight due to severe protein deficiency. PPARγ CD4cre+ mice on a control diet grew at rates similar to uninfected mice while nourished infected wild type (WT) mice experienced significant retardation in growth up to 11 days after challenge (Figure 1A–B).

Bottom Line: At the molecular level, both pharmacological blockade and deletion of PPARγ in T cells resulted in upregulation of TGF-β, IL-6, IL-17 and anti-microbial peptides, enhanced Th17 responses, fewer colonic lesions, faster clearance of EAEC, and improved recovery.The beneficial effects of PPARγ blockade on weight loss and EAEC clearance were abrogated by neutralizing IL-17 in vivo.Our studies provide in vivo evidence supporting the beneficial role of mucosal innate and effector T cell responses on EAEC burden and suggest pharmacological blockade of PPARγ as a novel therapeutic intervention for EAEC infection.

View Article: PubMed Central - PubMed

Affiliation: Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America.

ABSTRACT

Background: Enteroaggregative Escherichia coli (EAEC) is recognized as an emerging cause of persistent diarrhea and enteric disease worldwide. Mucosal immunity towards EAEC infections is incompletely understood due in part to the lack of appropriate animal models. This study presents a new mouse model and investigates the role of peroxisome proliferator-activated receptor gamma (PPARγ) in the modulation of host responses to EAEC in nourished and malnourished mice.

Methods/principal findings: Wild-type and T cell-specific PPARγ C57BL/6 mice were fed protein-deficient diets at weaning and challenged with 5×10(9)cfu EAEC strain JM221 to measure colonic gene expression and immune responses to EAEC. Antigen-specific responses to E. coli antigens were measured in nourished and malnourished mice following infection and demonstrated the immunosuppressive effects of malnutrition at the cellular level. At the molecular level, both pharmacological blockade and deletion of PPARγ in T cells resulted in upregulation of TGF-β, IL-6, IL-17 and anti-microbial peptides, enhanced Th17 responses, fewer colonic lesions, faster clearance of EAEC, and improved recovery. The beneficial effects of PPARγ blockade on weight loss and EAEC clearance were abrogated by neutralizing IL-17 in vivo.

Conclusions: Our studies provide in vivo evidence supporting the beneficial role of mucosal innate and effector T cell responses on EAEC burden and suggest pharmacological blockade of PPARγ as a novel therapeutic intervention for EAEC infection.

Show MeSH
Related in: MedlinePlus