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Selective ablation of Ctip2/Bcl11b in epidermal keratinocytes triggers atopic dermatitis-like skin inflammatory responses in adult mice.
PLoS One 2012; 7(12):e51262Plos

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.

METHODOLOGY/PRINCIPAL FINDINGS

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/SIGNIFICANCE

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+Show Affiliations

Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon, United States of America.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

23284675

Citation

Wang, Zhixing, et al. "Selective Ablation of Ctip2/Bcl11b in Epidermal Keratinocytes Triggers Atopic Dermatitis-like Skin Inflammatory Responses in Adult Mice." PloS One, vol. 7, no. 12, 2012, pp. e51262.
Wang Z, Zhang LJ, Guha G, et al. Selective ablation of Ctip2/Bcl11b in epidermal keratinocytes triggers atopic dermatitis-like skin inflammatory responses in adult mice. PLoS ONE. 2012;7(12):e51262.
Wang, Z., Zhang, L. J., Guha, G., Li, S., Kyrylkova, K., Kioussi, C., ... Indra, A. K. (2012). Selective ablation of Ctip2/Bcl11b in epidermal keratinocytes triggers atopic dermatitis-like skin inflammatory responses in adult mice. PloS One, 7(12), pp. e51262. doi:10.1371/journal.pone.0051262.
Wang Z, et al. Selective Ablation of Ctip2/Bcl11b in Epidermal Keratinocytes Triggers Atopic Dermatitis-like Skin Inflammatory Responses in Adult Mice. PLoS ONE. 2012;7(12):e51262. PubMed PMID: 23284675.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Selective ablation of Ctip2/Bcl11b in epidermal keratinocytes triggers atopic dermatitis-like skin inflammatory responses in adult mice. AU - Wang,Zhixing, AU - Zhang,Ling-Juan, AU - Guha,Gunjan, AU - Li,Shan, AU - Kyrylkova,Kateryna, AU - Kioussi,Chrissa, AU - Leid,Mark, AU - Ganguli-Indra,Gitali, AU - Indra,Arup K, Y1 - 2012/12/20/ PY - 2012/05/18/received PY - 2012/10/31/accepted PY - 2013/1/4/entrez PY - 2013/1/4/pubmed PY - 2013/6/19/medline SP - e51262 EP - e51262 JF - PloS one JO - PLoS ONE VL - 7 IS - 12 N2 - 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. METHODOLOGY/PRINCIPAL FINDINGS: 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/SIGNIFICANCE: 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. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/23284675/Selective_ablation_of_Ctip2/Bcl11b_in_epidermal_keratinocytes_triggers_atopic_dermatitis_like_skin_inflammatory_responses_in_adult_mice_ L2 - http://dx.plos.org/10.1371/journal.pone.0051262 DB - PRIME DP - Unbound Medicine ER -