title: Selective ablation of Ctip2/Bcl11b in epidermal keratinocytes triggers atopic dermatitis-like skin inflammatory responses in adult mice.
abstract: BACKGROUND
  Ctip2 is crucial for epidermal homeostasis and protective barrier formation in developing mouse embryos. Selective ablation of Ctip2 in epidermis leads to increased transepidermal water loss (TEWL), impaired epidermal proliferation, terminal differentiation, as well as altered lipid composition during development. However, little is known about the role of Ctip2 in skin homeostasis in adult mice.
  
  
  RESULTS
  To study the role of Ctip2 in adult skin homeostasis, we utilized Ctip2(ep-/-) mouse model in which Ctip2 is selectively deleted in epidermal keratinocytes. Measurement of TEWL, followed by histological, immunohistochemical, and RT-qPCR analyses revealed an important role of Ctip2 in barrier maintenance and in regulating adult skin homeostasis. We demonstrated that keratinocytic ablation of Ctip2 leads to atopic dermatitis (AD)-like skin inflammation, characterized by alopecia, pruritus and scaling, as well as extensive infiltration of immune cells including T lymphocytes, mast cells, and eosinophils. We observed increased expression of T-helper 2 (Th2)-type cytokines and chemokines in the mutant skin, as well as systemic immune responses that share similarity with human AD patients. Furthermore, we discovered that thymic stromal lymphopoietin (TSLP) expression was significantly upregulated in the mutant epidermis as early as postnatal day 1 and ChIP assay revealed that TSLP is likely a direct transcriptional target of Ctip2 in epidermal keratinocytes.
  
  
  CONCLUSIONS
  Our data demonstrated a cell-autonomous role of Ctip2 in barrier maintenance and epidermal homeostasis in adult mice skin. We discovered a crucial non-cell autonomous role of keratinocytic Ctip2 in suppressing skin inflammatory responses by regulating the expression of Th2-type cytokines. It is likely that the epidermal hyperproliferation in the Ctip2-lacking epidermis may be secondary to the compensatory response of the adult epidermis that is defective in barrier functions. Our results establish an initiating role of epidermal TSLP in AD pathogenesis via a novel repressive regulatory mechanism enforced by Ctip2.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon, United States of America.
authors.forename: Zhixing
authors.initials: Z
authors.lastname: Wang
authors.forename: Ling-Juan
authors.initials: LJ
authors.lastname: Zhang
authors.forename: Gunjan
authors.initials: G
authors.lastname: Guha
authors.forename: Shan
authors.initials: S
authors.lastname: Li
authors.forename: Kateryna
authors.initials: K
authors.lastname: Kyrylkova
authors.forename: Chrissa
authors.initials: C
authors.lastname: Kioussi
authors.forename: Mark
authors.initials: M
authors.lastname: Leid
authors.forename: Gitali
authors.initials: G
authors.lastname: Ganguli-Indra
authors.forename: Arup K
authors.initials: AK
authors.lastname: Indra
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004817:Epidermis / Q000473:pathology*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015603:Keratinocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D010539:Permeability; D012097:Repressor Proteins / Q000172:deficiency* / Q000235:genetics*; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics*; D000094632:Thymic Stromal Lymphopoietin
chemical_list: C511143:Bcl11b protein, mouse; D016207:Cytokines; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D000094632:Thymic Stromal Lymphopoietin