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Chronic airway-induced allergy in mice modifies gene expression in the brain toward insulin resistance and inflammatory responses.

Sarlus H, Wang X, Cedazo-Minguez A, Schultzberg M, Oprica M - J Neuroinflammation (2013)

Bottom Line: The aim of the present study was to obtain a global overview of the genes that drive the effects of peripheral inflammation associated with chronic airway-induced allergy in the brain.Quantitative polymerase chain reaction (qPCR) and protein analysis by Western blotting were performed for the validation of microarray results.We confirmed a reduction of insulin-degrading enzyme at the protein level and a decrease in insulin receptor phosphorylation in the brains of allergic mice.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurobiology, Care Sciences & Society, Division of Neurodegeneration, Karolinska Institutet, Novum, Floor 5, SE-141 86 Stockholm, Sweden. Heela.Sarlus@ki.se

ABSTRACT

Background: Chronic systemic inflammation affects brain functionality and may negatively influence the progression of neurodegenerative disorders. Allergy is a chronic inflammatory disease affecting more than 20% of the Western population. Little is known regarding the influence of allergy on brain functions. The aim of the present study was to obtain a global overview of the genes that drive the effects of peripheral inflammation associated with chronic airway-induced allergy in the brain.

Methods: Airway allergy was induced in C57B/6J mice using ovalbumin as the allergen. Microarray analysis was performed in the hippocampus and frontal cortex in association with Affymetrix. For the data analysis, principal component analysis and orthogonal to latent structures discriminant analysis followed by pathway analysis were used. Quantitative polymerase chain reaction (qPCR) and protein analysis by Western blotting were performed for the validation of microarray results.

Results: Microarray analysis showed low-grade changes in gene expression in the brain induced by airway-associated allergy. Changes in expression were observed for genes involved in antigen processing and presentation, cytokine-cytokine interaction, Toll-like receptor and mitogen-activated protein kinase signaling, as determined by pathway analysis. We confirmed a reduction of insulin-degrading enzyme at the protein level and a decrease in insulin receptor phosphorylation in the brains of allergic mice. Other allergy-induced gene expression changes were confirmed by qPCR, including increased levels of tumor necrosis factor receptor superfamily member 23 and lipopolysaccharide-binding protein.

Conclusion: Airway-associated allergy induces changes in brain gene expression toward induction of insulin resistance and inflammatory responses with potential implications for neurodegenerative disorders.

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Allergy decreases the levels of insulin-degrading enzyme (IDE) in the mouse brain. Western blot analysis showed a decrease in IDE levels in the hippocampus (A), frontal cortex (B) and hypothalamus of allergic mice compared to controls (C). The data were analyzed using Student’s t-test. The boxplot indicates the first two quartiles with the median, and the whiskers indicate the third and fourth quartiles (n = 8 mice per group). Only six control mice were used for the hypothalamus because two samples were lost during sonication. The images below the graph indicate the immunoblotting of IDE. Asterisk, p < 0.05, triple asterisk p < 0.001.
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Figure 5: Allergy decreases the levels of insulin-degrading enzyme (IDE) in the mouse brain. Western blot analysis showed a decrease in IDE levels in the hippocampus (A), frontal cortex (B) and hypothalamus of allergic mice compared to controls (C). The data were analyzed using Student’s t-test. The boxplot indicates the first two quartiles with the median, and the whiskers indicate the third and fourth quartiles (n = 8 mice per group). Only six control mice were used for the hypothalamus because two samples were lost during sonication. The images below the graph indicate the immunoblotting of IDE. Asterisk, p < 0.05, triple asterisk p < 0.001.

Mentions: The microarray data showed that allergy was associated with a reduction in IDE, which mediates cleavage of insulin and amyloid-β (Aβ), important proteins in diabetes mellitus and AD, respectively. Western blot analysis of the protein levels showed a significant decrease in IDE in both the hippocampus (Figure 5A) [95% confidence interval (CI) 0.64-1.57; P < 0.001] and the frontal cortex (Figure 5B) [95% CI 1.19-2.82; P < 0.001] of allergic mice compared to controls. Since insulin signaling in the hypothalamus plays an important role in the regulation of glucose metabolism, the hypothalamic IDE levels were measured. The IDE levels were significantly reduced in the hypothalamus from allergic mice [95% CI 0.59-0.66;P < 0.05] (Figure 5C). As insulin is a major substrate for IDE, we further analyzed whether changes in IDE could have a functional impact on insulin signaling. The levels and phosphorylation status of IRs were analyzed by immunoblotting. t-IR levels were similar in allergic and control mice; however, allergy was associated with a significant decrease in the levels of p-IR [95% CI 0.01- 0.31;P < 0.05] in the hippocampus (Figure 6) but not in the frontal cortex and hypothalamus, although the data showed a trend similar to that in the hippocampus (data not shown). We also analyzed the expression of transthyretin and TRH by qPCR; however, we found no changes between the groups (data not shown), as indicated by the microarray data.


Chronic airway-induced allergy in mice modifies gene expression in the brain toward insulin resistance and inflammatory responses.

Sarlus H, Wang X, Cedazo-Minguez A, Schultzberg M, Oprica M - J Neuroinflammation (2013)

Allergy decreases the levels of insulin-degrading enzyme (IDE) in the mouse brain. Western blot analysis showed a decrease in IDE levels in the hippocampus (A), frontal cortex (B) and hypothalamus of allergic mice compared to controls (C). The data were analyzed using Student’s t-test. The boxplot indicates the first two quartiles with the median, and the whiskers indicate the third and fourth quartiles (n = 8 mice per group). Only six control mice were used for the hypothalamus because two samples were lost during sonication. The images below the graph indicate the immunoblotting of IDE. Asterisk, p < 0.05, triple asterisk p < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3750454&req=5

Figure 5: Allergy decreases the levels of insulin-degrading enzyme (IDE) in the mouse brain. Western blot analysis showed a decrease in IDE levels in the hippocampus (A), frontal cortex (B) and hypothalamus of allergic mice compared to controls (C). The data were analyzed using Student’s t-test. The boxplot indicates the first two quartiles with the median, and the whiskers indicate the third and fourth quartiles (n = 8 mice per group). Only six control mice were used for the hypothalamus because two samples were lost during sonication. The images below the graph indicate the immunoblotting of IDE. Asterisk, p < 0.05, triple asterisk p < 0.001.
Mentions: The microarray data showed that allergy was associated with a reduction in IDE, which mediates cleavage of insulin and amyloid-β (Aβ), important proteins in diabetes mellitus and AD, respectively. Western blot analysis of the protein levels showed a significant decrease in IDE in both the hippocampus (Figure 5A) [95% confidence interval (CI) 0.64-1.57; P < 0.001] and the frontal cortex (Figure 5B) [95% CI 1.19-2.82; P < 0.001] of allergic mice compared to controls. Since insulin signaling in the hypothalamus plays an important role in the regulation of glucose metabolism, the hypothalamic IDE levels were measured. The IDE levels were significantly reduced in the hypothalamus from allergic mice [95% CI 0.59-0.66;P < 0.05] (Figure 5C). As insulin is a major substrate for IDE, we further analyzed whether changes in IDE could have a functional impact on insulin signaling. The levels and phosphorylation status of IRs were analyzed by immunoblotting. t-IR levels were similar in allergic and control mice; however, allergy was associated with a significant decrease in the levels of p-IR [95% CI 0.01- 0.31;P < 0.05] in the hippocampus (Figure 6) but not in the frontal cortex and hypothalamus, although the data showed a trend similar to that in the hippocampus (data not shown). We also analyzed the expression of transthyretin and TRH by qPCR; however, we found no changes between the groups (data not shown), as indicated by the microarray data.

Bottom Line: The aim of the present study was to obtain a global overview of the genes that drive the effects of peripheral inflammation associated with chronic airway-induced allergy in the brain.Quantitative polymerase chain reaction (qPCR) and protein analysis by Western blotting were performed for the validation of microarray results.We confirmed a reduction of insulin-degrading enzyme at the protein level and a decrease in insulin receptor phosphorylation in the brains of allergic mice.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurobiology, Care Sciences & Society, Division of Neurodegeneration, Karolinska Institutet, Novum, Floor 5, SE-141 86 Stockholm, Sweden. Heela.Sarlus@ki.se

ABSTRACT

Background: Chronic systemic inflammation affects brain functionality and may negatively influence the progression of neurodegenerative disorders. Allergy is a chronic inflammatory disease affecting more than 20% of the Western population. Little is known regarding the influence of allergy on brain functions. The aim of the present study was to obtain a global overview of the genes that drive the effects of peripheral inflammation associated with chronic airway-induced allergy in the brain.

Methods: Airway allergy was induced in C57B/6J mice using ovalbumin as the allergen. Microarray analysis was performed in the hippocampus and frontal cortex in association with Affymetrix. For the data analysis, principal component analysis and orthogonal to latent structures discriminant analysis followed by pathway analysis were used. Quantitative polymerase chain reaction (qPCR) and protein analysis by Western blotting were performed for the validation of microarray results.

Results: Microarray analysis showed low-grade changes in gene expression in the brain induced by airway-associated allergy. Changes in expression were observed for genes involved in antigen processing and presentation, cytokine-cytokine interaction, Toll-like receptor and mitogen-activated protein kinase signaling, as determined by pathway analysis. We confirmed a reduction of insulin-degrading enzyme at the protein level and a decrease in insulin receptor phosphorylation in the brains of allergic mice. Other allergy-induced gene expression changes were confirmed by qPCR, including increased levels of tumor necrosis factor receptor superfamily member 23 and lipopolysaccharide-binding protein.

Conclusion: Airway-associated allergy induces changes in brain gene expression toward induction of insulin resistance and inflammatory responses with potential implications for neurodegenerative disorders.

Show MeSH
Related in: MedlinePlus