ΔNp63 Regulates IL-33 and IL-31 Signaling in Atopic Dermatitis

Overview

Journal Cell Death Differ

Specialty Cell Biology

Date 2016 Jan 16

PMID 26768665

Citations 27

Authors

J M Rizzo

A Oyelakin

S Min

K Smalley

J Bard

W Luo

J Nyquist

E Guttman-Yassky

T Yoshida

A De Benedetto

L A Beck

S Sinha

R-A Romano

Affiliations

Soon will be listed here.

Abstract

Atopic dermatitis (AD) is the most common inflammatory skin disease with no well-delineated cause or effective cure. Here we show that the p53 family member p63, specifically the ΔNp63, isoform has a key role in driving keratinocyte activation in AD. We find that overexpression of ΔNp63 in transgenic mouse epidermis results in a severe skin phenotype that shares many of the key clinical, histological and molecular features associated with human AD. This includes pruritus, epidermal hyperplasia, aberrant keratinocyte differentiation, enhanced expression of selected cytokines and chemokines and the infiltration of large numbers of inflammatory cells including type 2 T-helper cells - features that are highly representative of AD dermatopathology. We further demonstrate several of these mediators to be direct transcriptional targets of ΔNp63 in keratinocytes. Of particular significance are two p63 target genes, IL-31 and IL-33, both of which are key players in the signaling pathways implicated in AD. Importantly, we find these observations to be in good agreement with elevated levels of ΔNp63 in skin lesions of human patients with AD. Our studies reveal an important role for ΔNp63 in the pathogenesis of AD and offer new insights into its etiology and possible therapeutic targets.

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References

Heintzman N, Stuart R, Hon G, Fu Y, Ching C, Hawkins R . Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat Genet. 2007; 39(3):311-8. DOI: 10.1038/ng1966. View

Akei H, Brandt E, Mishra A, Strait R, Finkelman F, Warrier M . Epicutaneous aeroallergen exposure induces systemic TH2 immunity that predisposes to allergic nasal responses. J Allergy Clin Immunol. 2006; 118(1):62-9. DOI: 10.1016/j.jaci.2006.04.046. View

Dillon S, Sprecher C, Hammond A, Bilsborough J, Rosenfeld-Franklin M, Presnell S . Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice. Nat Immunol. 2004; 5(7):752-60. DOI: 10.1038/ni1084. View

Romano R, Birkaya B, Sinha S . A functional enhancer of keratin14 is a direct transcriptional target of deltaNp63. J Invest Dermatol. 2006; 127(5):1175-86. DOI: 10.1038/sj.jid.5700652. View

. A user's guide to the encyclopedia of DNA elements (ENCODE). PLoS Biol. 2011; 9(4):e1001046. PMC: 3079585. DOI: 10.1371/journal.pbio.1001046. View

Tokura Y . Extrinsic and intrinsic types of atopic dermatitis. J Dermatol Sci. 2010; 58(1):1-7. DOI: 10.1016/j.jdermsci.2010.02.008. View

Cornelissen C, Marquardt Y, Czaja K, Wenzel J, Frank J, Luscher-Firzlaff J . IL-31 regulates differentiation and filaggrin expression in human organotypic skin models. J Allergy Clin Immunol. 2011; 129(2):426-33, 433.e1-8. DOI: 10.1016/j.jaci.2011.10.042. View

Salimi M, Barlow J, Saunders S, Xue L, Gutowska-Owsiak D, Wang X . A role for IL-25 and IL-33-driven type-2 innate lymphoid cells in atopic dermatitis. J Exp Med. 2013; 210(13):2939-50. PMC: 3865470. DOI: 10.1084/jem.20130351. View

Szegedi K, Kremer A, Kezic S, Teunissen M, Bos J, Luiten R . Increased frequencies of IL-31-producing T cells are found in chronic atopic dermatitis skin. Exp Dermatol. 2012; 21(6):431-6. DOI: 10.1111/j.1600-0625.2012.01487.x. View

10.

Birney E, Stamatoyannopoulos J, Dutta A, Guigo R, Gingeras T, Margulies E . Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature. 2007; 447(7146):799-816. PMC: 2212820. DOI: 10.1038/nature05874. View

11.

Boguniewicz M, Leung D . Atopic dermatitis: a disease of altered skin barrier and immune dysregulation. Immunol Rev. 2011; 242(1):233-46. PMC: 3122139. DOI: 10.1111/j.1600-065X.2011.01027.x. View

12.

Stott B, Lavender P, Lehmann S, Pennino D, Durham S, Schmidt-Weber C . Human IL-31 is induced by IL-4 and promotes TH2-driven inflammation. J Allergy Clin Immunol. 2013; 132(2):446-54.e5. DOI: 10.1016/j.jaci.2013.03.050. View

13.

Mills A, Zheng B, Wang X, Vogel H, Roop D, Bradley A . p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature. 1999; 398(6729):708-13. DOI: 10.1038/19531. View

14.

Ha L, Ponnamperuma R, Jay S, Ricci M, Weinberg W . Dysregulated ΔNp63α inhibits expression of Ink4a/arf, blocks senescence, and promotes malignant conversion of keratinocytes. PLoS One. 2011; 6(7):e21877. PMC: 3137598. DOI: 10.1371/journal.pone.0021877. View

15.

Romano R, Birkaya B, Sinha S . Defining the regulatory elements in the proximal promoter of DeltaNp63 in keratinocytes: Potential roles for Sp1/Sp3, NF-Y, and p63. J Invest Dermatol. 2006; 126(7):1469-79. DOI: 10.1038/sj.jid.5700297. View

16.

Imai Y, Yasuda K, Sakaguchi Y, Haneda T, Mizutani H, Yoshimoto T . Skin-specific expression of IL-33 activates group 2 innate lymphoid cells and elicits atopic dermatitis-like inflammation in mice. Proc Natl Acad Sci U S A. 2013; 110(34):13921-6. PMC: 3752227. DOI: 10.1073/pnas.1307321110. View

17.

Leung D, Hirsch R, Schneider L, Moody C, Takaoka R, Li S . Thymopentin therapy reduces the clinical severity of atopic dermatitis. J Allergy Clin Immunol. 1990; 85(5):927-33. DOI: 10.1016/0091-6749(90)90079-j. View

18.

Leung D, Bieber T . Atopic dermatitis. Lancet. 2003; 361(9352):151-60. DOI: 10.1016/S0140-6736(03)12193-9. View

19.

Senoo M, Pinto F, Crum C, McKeon F . p63 Is essential for the proliferative potential of stem cells in stratified epithelia. Cell. 2007; 129(3):523-36. DOI: 10.1016/j.cell.2007.02.045. View

20.

Trapnell C, Hendrickson D, Sauvageau M, Goff L, Rinn J, Pachter L . Differential analysis of gene regulation at transcript resolution with RNA-seq. Nat Biotechnol. 2012; 31(1):46-53. PMC: 3869392. DOI: 10.1038/nbt.2450. View