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Induction of Murine Intestinal Inflammation by Adoptive Transfer of Effector CD4+CD45RBhigh T Cells into Immunodeficient Mice
Published on: April 21, 2015
CARD14 signaling in intestinal epithelial cells induces intestinal inflammation and intestinal transit delay
Aigerim Aidarova1,2, Marieke Carels1,2, Mira Haegman1,2
1Center for Inflammation Research, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent, Belgium.
Insights
Gain-of-function CARD14 mutations in intestinal epithelial cells (IEC) cause mild inflammation and reduced motility in mice. This suggests a link between psoriasis-associated CARD14 variants and intestinal disorders, impacting gut health and infection susceptibility.
Area of Science:
- Gastroenterology
- Immunology
- Genetics
Background:
- CARD14 is an NF-κB signaling mediator primarily known for its role in skin immunity.
- Rare CARD14 variants are linked to skin conditions like psoriasis and atopic dermatitis.
- CARD14 expression in intestinal epithelial cells (IEC) suggests a potential role in gut function, which remains unexplored.
Purpose of the Study:
- To investigate the function of CARD14 in the intestine, specifically in IEC.
- To determine the effects of a psoriasis-associated CARD14 gain-of-function mutation in the gut.
- To explore the link between CARD14 variants and intestinal inflammation, motility, and infection susceptibility.
Main Methods:
- Generated transgenic mice expressing the human CARD14(E138A) gain-of-function mutant specifically in IEC (CARD14(E138A)IEC mice).
- Assessed intestinal inflammation, epithelial integrity, and enteric neuronal function.
- Analyzed intestinal motility, gut microbiota composition, and susceptibility to enteric bacterial infection.
- Performed transcriptome analysis of IEC to identify molecular changes.
Main Results:
- CARD14(E138A)IEC mice exhibited mild intestinal inflammation without epithelial damage.
- A significant reduction in intestinal motility and rectal prolapse were observed.
- Enteric neuronal survival and function remained unaffected.
- Decreased expression of antimicrobial peptides by Paneth cells, microbial dysbiosis, and increased susceptibility to enteric infection were noted.
- Transcriptome analysis revealed altered gene expression in IEC.
Conclusions:
- Gain-of-function CARD14 mutations in IEC can lead to mild intestinal inflammation and reduced motility.
- These findings suggest that psoriasis-associated CARD14 variants may predispose individuals to intestinal disorders.
- CARD14(E138A)IEC mice serve as a valuable model for studying IEC-intrinsic mechanisms in intestinal inflammation and motility disorders.
Abstract:
CARD14 is an intracellular NF-κB signaling mediator in the skin, and rare CARD14 variants have been associated with psoriasis and atopic dermatitis. CARD14 is also expressed in intestinal epithelial cells (IEC). However, its function in the intestine remains unknown. We demonstrate here that transgenic mice expressing the psoriasis-associated gain-of-function human CARD14(E138A) mutant specifically in IEC show mild intestinal inflammation, without epithelial damage. Moreover, CARD14(E138A)IEC mice show a drastic reduction in intestinal motility, often associated with rectal prolapse. Enteric neuronal survival and functionality are unaffected in CARD14(E138A)IEC mice. Transcriptome analysis of IEC from CARD14(E138A)IEC mice reveals decreased expression of antimicrobial peptides by Paneth cells, accompanied by microbial dysbiosis and increased susceptibility to enteric bacterial infection. Our findings suggest that gain-of-function CARD14 mutations may not only predispose patients to psoriasis but also mild intestinal inflammation, reduced intestinal motility, and increased sensitivity to intestinal infection. CARD14(E138A)IEC mice are also a valuable tool for further investigation of IEC-intrinsic molecular processes involved in intestinal inflammation and motility disorders.
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