title: Hematopoietic plakophilin-3 regulates acute tissue-specific and systemic inflammation in mice.
abstract: Plakophilin-3 (PKP3) is a member of the armadillo protein family, which is important in cell-cell contacts and signaling during development and tumorigenesis. In conventional facilities, PKP3-deficient mice (PKP3(-/-)) develop spontaneous dermatitis, indicating a possible involvement of PKP3 in inflammatory responses. Here, we show that PKP3 deficiency sensitizes mice to irritant contact dermatitis induced by phorbol myristate acetate (PMA). This sensitization occurred in mice with PKP3 deficiency in the hematopoietic system (PKP3(-/-hem)), but not if the deficiency was specific to skin keratinocytes (PKP3(-/-ker)). In a model of dextran sulfate sodium induced colitis, ubiquitous PKP3 deletion, but not intestinal epithelial PKP3 deficiency (PKP3(-/-IEC)), impaired survival from disease. Interestingly, PKP3(-/-hem) mice also displayed increased sensitivity to dextran sulfate sodium induced colitis. Finally, PKP3(-/-) mice were more sensitive to the lethality of lipopolysaccharide (LPS) injection than wild-type (WT) mice, and this phenotype was associated with increased intestinal permeability. PKP3(-/-IEC) mice did not reproduce the enhanced endotoxin reactivity of PKP3(-/-) mice, in contrast to PKP3(-/-hem) mice. Finally, in vitro stimulation of WT neutrophils with LPS or PMA increased Pkp3 expression. In conclusion, our data highlight a novel role for hematopoietic PKP3 in the regulation of both locally and systemically induced immune responses. Nonetheless, further research is needed to unravel the underlying mechanism.
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Sklyarova
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.|Department of Basic Medical Sciences, Ghent University, Ghent, Belgium.
authors.forename: Jolanda
authors.initials: J
authors.lastname: van Hengel
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Elien
authors.initials: E
authors.lastname: Van Wonterghem
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Claude
authors.initials: C
authors.lastname: Libert
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Frans
authors.initials: F
authors.lastname: van Roy
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Roosmarijn E
authors.initials: RE
authors.lastname: Vandenbroucke
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000276:immunology*; D003877:Dermatitis, Contact / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D051191:Plakophilins / Q000235:genetics / Q000276:immunology*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
chemical_list: D008070:Lipopolysaccharides; C495340:Pkp3 protein, mouse; D051191:Plakophilins; D016264:Dextran Sulfate; D013755:Tetradecanoylphorbol Acetate
keywords: Acute inflammation; Colitis; Dermatitis; Hematopoietic cell; Intestine; Plakophilin-3; Sepsis; Skin