title: Conditional PDK1 Ablation Promotes Epidermal and T-Cell-Mediated Dysfunctions Leading to Inflammatory Skin Disease.
abstract: Phosphoinositide-dependent kinase-1 (PDK1) is a key signaling molecule downstream of the phosphatidylinositol 3-kinase pathway and is a master regulator of multiple kinases in cells of epithelial and hematopoietic lineages. The physiological role of PDK1 in regulating skin and immune homeostasis is not known. Here we developed a mouse model in which PDK1 is conditionally ablated in activated CD4 T cells, regulatory T cells, and mature keratinocytes through OX40-Cre recombinase expression. The resultant mice (PDK1-CKO) spontaneously developed severe dermatitis, skin fibrosis, and systemic T helper type 2 immunity, succumbing by 11 weeks of age. Through a series of T-cell transfers, bone marrow reconstitutions, and crossing to lymphocyte-deficient backgrounds, we demonstrate that ablation of PDK1 in keratinocytes is the major driver of disease pathogenesis. PDK1-deficient keratinocytes exhibit intrinsic defects in the expression of key structural proteins including cytokeratin-10 and loricrin, resulting in increased keratinocyte turnover, which in turn triggers inflammation, T-cell recruitment, and immune-mediated destruction. Our results reveal PDK1 as a central regulator of keratinocyte homeostasis that prevents skin immune infiltration and inflammation.
authors.affiliation: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, New York, USA; Department of Medicine, Columbia University, New York, New York, USA.
authors.forename: Minjun
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of Dermatology, Columbia University, New York, New York, USA; Department of Pathology and Cell Biology, Columbia University, New York, New York, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Owens
authors.affiliation: Department of Microbiology and Immunology, Columbia University, New York, New York, USA.
authors.forename: Sankar
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, New York, USA; Department of Microbiology and Immunology, Columbia University, New York, New York, USA; Department of Surgery, Columbia University, New York, New York, USA. Electronic address: df2396@cumc.columbia.edu.
authors.forename: Donna L
authors.initials: DL
authors.lastname: Farber
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003872:Dermatitis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D004817:Epidermis / Q000378:metabolism; D005434:Flow Cytometry; D017353:Gene Deletion; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011897:Random Allocation; D012680:Sensitivity and Specificity; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
chemical_list: C000631433:Pdk1 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017346:Protein Serine-Threonine Kinases