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Model of colonic inflammation: immune modulatory mechanisms in inflammatory bowel disease.

ABSTRACT: Inflammatory bowel disease (IBD) is an immunoinflammatory illness of the gut initiated by an immune response to bacteria in the microflora. The resulting immunopathogenesis leads to lesions in epithelial lining of the colon through which bacteria may infiltrate the tissue causing recurring bouts of diarrhea, rectal bleeding, and malnutrition. In healthy individuals such immunopathogenesis is avoided by the presence of regulatory cells that inhibit the inflammatory pathway. Highly relevant to the search for treatment strategies is the identification of components of the inflammatory pathway that allow regulatory mechanisms to be overridden and immunopathogenesis to proceed. In vitro techniques have identified cellular interactions involved in inflammation-regulation crosstalk. However, tracing immunological mechanisms discovered at the cellular level confidently back to an in vivo context of multiple, simultaneous interactions has met limited success. To explore the impact of specific interactions, we have constructed a system of 29 ordinary differential equations representing different phenotypes of T-cells, macrophages, dendritic cells, and epithelial cells as they move and interact with bacteria in the lumen, lamina propria, and lymphoid tissue of the colon. Simulations revealed the positive inflammatory feedback loop formed by inflammatory M1 macrophage activation of T-cells as a driving force underlying the immunopathology of IBD. Furthermore, strategies that remove M1 from the site of infection, by either (i) increasing its potential to switch to a regulatory M2 phenotype or (ii) increasing the rate of reversion (for M1 and M2 alike) to a resting state, cease immunopathogenesis even as bacteria are eliminated by other inflammatory cells. Based on these results, we identify macrophages and their mechanisms of plasticity as key targets for mucosal inflammation intervention strategies. In addition, we propose that the primary mechanism behind the association of PPARgamma mutation with IBD is its ability to mediate the M1 to M2 switch.

SUBMITTER: Wendelsdorf K

PROVIDER: S-EPMC2878745 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Model of colonic inflammation: immune modulatory mechanisms in inflammatory bowel disease.

Wendelsdorf Katherine K Bassaganya-Riera Josep J Hontecillas Raquel R Eubank Stephen S

Journal of theoretical biology 20100401 4

Inflammatory bowel disease (IBD) is an immunoinflammatory illness of the gut initiated by an immune response to bacteria in the microflora. The resulting immunopathogenesis leads to lesions in epithelial lining of the colon through which bacteria may infiltrate the tissue causing recurring bouts of diarrhea, rectal bleeding, and malnutrition. In healthy individuals such immunopathogenesis is avoided by the presence of regulatory cells that inhibit the inflammatory pathway. Highly relevant to the ...[more]

PMID: 20362587

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Project description:Introduction: Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract and encompasses Crohn's Disease and Ulcerative Colitis. Women appear to have more severe and recurring symptoms of IBD compared to men, most likely due to hormonal fluctuations. Studies have shown that mitochondrial dysfunction plays a role in the development of inflammation and there is evidence of colon mitochondrial alterations in IBD models and patients. In this study we have identified the presence of sex-specific colon mitochondrial dysfunction in a rat model of IBD. Methods: Eight-week-old male and female rats were treated with indomethacin to induce IBD and mitoTEMPO was administered daily either after or before induction of IBD and until euthanasia. Colons were collected for histology and mitochondrial experiments. Intact mitochondrial respiration, reactive oxygen species (mtROS), the activities of the individual electron transport complexes and the activities of the antioxidant enzymes were measured to assess mitochondrial function. Results: IBD male rats showed a decrease in citrate synthase activity, cardiolipin levels, catalase activity and an increase in mtROS production. IBD females show a decrease in intact colon mitochondrial respiration, colon mitochondria respiratory control ratio (RCR), complex I activity, complex IV activity, and an increase in mtROS. Interestingly, control females showed a significantly higher rate of complex I and II-driven intact mitochondrial respiration, MCFA oxidation, complex II activity, complex III activity, and complex IV activity compared to control males. The use of a mitochondrial-targeted therapy, mitoTEMPO, improved the disease and colon mitochondrial function in female IBD rats. However, in the males there was no observed improvement, likely due to the decrease in catalase activity. Conclusion: Our study provides a better understanding of the role mitochondria in the development of IBD and highlights sex differences in colon mitochondrial function. It also opens an avenue for the development of strategies to re-establish normal mitochondrial function that could provide more options for preventive and therapeutic interventions for IBD.

Dataset Information

Model of colonic inflammation: immune modulatory mechanisms in inflammatory bowel disease.

Publications

Model of colonic inflammation: immune modulatory mechanisms in inflammatory bowel disease.

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