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CARD14 signaling in intestinal epithelial cells induces intestinal inflammation and intestinal transit delay

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 is 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 with 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 a valuable tool for further investigation of IEC-intrinsic molecular processes involved in intestinal inflammation and motility disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE302705 | GEO | 2025/09/17

REPOSITORIES: GEO

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Project description:Histone deacetylases (Hdac) remove acetyl groups from proteins, influencing global and specific gene expression. Hdacs control inflammation, as shown by Hdac inhibitor-dependent protection from DSS-induced murine colitis. While tissue-specific Hdac knockouts show redundant and specific functions, little is known of their intestinal epithelial cell (IEC) role. We have shown previously that dual Hdac1/Hdac2 IEC-specific loss disrupts cell proliferation and determination, with decreased secretory cell numbers and altered barrier function. We thus investigated how compound Hdac1/Hdac2 or Hdac2 IEC-specific deficiency alters the inflammatory response. Floxed Hdac1 and Hdac2 and villin-Cre mice were interbred. Compound Hdac1/Hdac2 IEC-deficient mice showed chronic basal inflammation, with increased basal Disease Activity Index (DAI) and deregulated Reg gene colonic expression. DSS-treated dual Hdac1/Hdac2 IEC-deficient mice displayed increased DAI, histological score, intestinal permeability and inflammatory gene expression. In contrast to double knockouts, Hdac2 IEC-specific loss did not affect IEC determination and growth, nor result in chronic inflammation. However, Hdac2 disruption protected against DSS colitis, as shown by decreased DAI, intestinal permeability and caspase-3 cleavage. Hdac2 IEC-specific deficient mice displayed increased expression of IEC gene subsets, such as colonic antimicrobial Reg3b and Reg3g mRNAs, and decreased expression of immune cell function-related genes. Our data show that Hdac1 and Hdac2 are essential IEC homeostasis regulators. IEC-specific Hdac1 and Hdac2 may act as epigenetic sensors and transmitters of environmental cues and regulate IEC-mediated mucosal homeostatic and inflammatory responses. Different levels of IEC Hdac activity may lead to positive or negative outcomes on intestinal homeostasis during inflammation Total RNAs from the colon of three control and three Hdac2 IEC-specific knockout mice were isolated with the Rneasy kit (Qiagen, Mississauga, ON, Canada).

Project description:Psoriasis is a common, immune-mediated, genetic disorder of the skin associated with arthritis in approximately 30% of cases. Previously, we localized PSORS2 (psoriasis susceptibility locus 2) to chromosome 17q25.3-qter following a genome-wide linkage scan in a family of European origin with multiple cases of psoriasis and psoriatic arthritis. Linkage to PSORS2 was also observed in a multiply affected psoriasis family from Taiwan. With genomic capture and DNA sequencing, we identified unique gain-of-function mutations in caspase recruitment domain family, member 14 (CARD14) that segregated with psoriasis. The mutations, c.349G>A (p.Gly117Ser) and c.349+5G>A respectively, altered splicing between exons 3 and 4 of CARD14. A de novo mutation in CARD14, c.413A>C [p.Glu138Ala], was detected in a child with sporadic, early-onset, generalized pustular psoriasis. CARD14 activates nuclear factor kappa B (NF-kB), and the p.Gly117Ser and p.Glu138Ala substitutions were shown to lead to enhanced NF-kB activation and upregulation of a subset of psoriasis-associated genes in keratinocytes compared to wildtype CARD14. These included chemokine (C-C motif) ligand 20 (CCL20) and interleukin 8 (IL8). CARD14 is localized mainly in the basal and suprabasal layers of healthy skin epidermis, while in lesional psoriatic skin it is reduced in the basal layer and more diffusely upregulated in the suprabasal layers of the lesional epidermis. We propose that, following a triggering event that can include epidermal injury, rare gain-of-function mutations in CARD14 initiate a process that includes inflammatory cell recruitment by keratinocytes. This perpetuates a vicious cycle of epidermal inflammation and regeneration that is the hallmark of psoriasis. No replicates are included. Three sample sets. [1] Skin biopsies had RNA extracted for expression within target tissue. [2] HEK cells were transfected with different constructs (including wildtype) of CARD14 to determine the mutational effect in keratinocytes. [3] Keratinocytes derived from psoriasis patients with CARD14 mutations were cultured and compared with and without stimulation with TNFalpha.

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CARD14 signaling in intestinal epithelial cells induces intestinal inflammation and intestinal transit delay

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