Viladomiu2012 - PPARgamma role in C.diff associated disease
"Modeling the Role of Peroxisome Proliferator-Activated Receptor γ and MicroRNA-146 in Mucosal Immune Responses to Clostridium difficile" Monica Viladomiu1,2, Raquel Hontecillas1,2, Mireia Pedragosa1,2, Adria Carbo1,2, Stefan Hoops1,2, Pawel Michalak4,5, Katarzyna Michalak4, Richard L. Guerrant2,3, James K. Roche2,3, Cirle A. Warren2,3, Josep Bassaganya-Riera1,2* 1) Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America, 2) Center for Modeling Immunity to Enteric Pathogens, Virginia Tech, Blacksburg, Virginia, United States of America, 3) Division of Infectious Disease and International Health, Center for Global Health, University of Virginia, Charlottesville, Virginia, United States of America, 4) Medical Informatics and Systems Division, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America, 5) Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia, United States of America E-mail: firstname.lastname@example.org This model represents the interaction between Cdiff, miRNA146b, NCOA4, PPARg, IL10 and IL17. Simulation studies show an aberrant expression of miRNA146b with increasing concentrations of Cdiff over time, which results in decreased PPARg activation due to NCOA4 inhibition. As a final result, PPARg is unable to modulate effector and regulatory responses, since results show an upregulation of IL17 expression and downregulation of IL10 production.
- Modeling the role of peroxisome proliferator-activated receptor γ and microRNA-146 in mucosal immune responses to Clostridium difficile.
- Viladomiu M, Hontecillas R, Pedragosa M, Carbo A, Hoops S, Michalak P, Michalak K, Guerrant RL, Roche JK, Warren CA, Bassaganya-Riera J
- PloS one , 0/ 2012 , Volume 7 , pages: e47525 , PubMed ID: 23071818
- Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, VA, USA.
- Clostridium difficile is an anaerobic bacterium that has re-emerged as a facultative pathogen and can cause nosocomial diarrhea, colitis or even death. Peroxisome proliferator-activated receptor (PPAR) γ has been implicated in the prevention of inflammation in autoimmune and infectious diseases; however, its role in the immunoregulatory mechanisms modulating host responses to C. difficile and its toxins remains largely unknown. To characterize the role of PPARγ in C. difficile-associated disease (CDAD), immunity and gut pathology, we used a mouse model of C. difficile infection in wild-type and T cell-specific PPARγ null mice. The loss of PPARγ in T cells increased disease activity and colonic inflammatory lesions following C. difficile infection. Colonic expression of IL-17 was upregulated and IL-10 downregulated in colons of T cell-specific PPARγ null mice. Also, both the loss of PPARγ in T cells and C. difficile infection favored Th17 responses in spleen and colonic lamina propria of mice with CDAD. MicroRNA (miRNA)-sequencing analysis and RT-PCR validation indicated that miR-146b was significantly overexpressed and nuclear receptor co-activator 4 (NCOA4) suppressed in colons of C. difficile-infected mice. We next developed a computational model that predicts the upregulation of miR-146b, downregulation of the PPARγ co-activator NCOA4, and PPARγ, leading to upregulation of IL-17. Oral treatment of C. difficile-infected mice with the PPARγ agonist pioglitazone ameliorated colitis and suppressed pro-inflammatory gene expression. In conclusion, our data indicates that miRNA-146b and PPARγ activation may be implicated in the regulation of Th17 responses and colitis in C. difficile-infected mice.
Submitter of this revision: Monica Viladomiu
Modellers: Monica Viladomiu
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- Model originally submitted by : Monica Viladomiu
- Submitted: Oct 26, 2012 5:02:23 PM
- Last Modified: Nov 22, 2012 2:11:26 PM
- Submitted on: Nov 22, 2012 2:11:26 PM
- Submitted by: Monica Viladomiu
- With comment: Current version of Viladomiu2012 - PPARgamma role in C.diff associated disease
- Submitted on: Oct 26, 2012 5:02:23 PM
- Submitted by: Monica Viladomiu
- With comment: Original import of NoName
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