Loss of Sirtuin 1 (SIRT1) Disrupts Skin Barrier Integrity and Sensitizes Mice to Epicutaneous Allergen Challenge

Overview

Journal J Allergy Clin Immunol

Specialty Allergy & Immunology

Date 2014 Dec 3

PMID 25445829

Citations 32

Authors

Mei Ming

Baozhong Zhao

Christopher R Shea

Palak Shah

Lei Qiang

Steven R White

Diane M Sims

Yu-Ying He

Affiliations

Soon will be listed here.

Abstract

Background: Skin barrier integrity requires a highly coordinated molecular system involving the structural protein filaggrin (FLG). Mutational loss of the skin barrier protein FLG predisposes subjects to the development of atopic dermatitis (AD).

Objective: We sought to determine the role of sirtuin 1 (SIRT1) in skin barrier function, FLG expression, and development of AD.

Methods: Skin histology of mice with skin-specific SIRT1 deletion and wild-type control animals was examined by using hematoxylin and eosin staining. Protein and mRNA abundance was analyzed by means of immunoblotting, immunohistochemistry, immunofluorescence, and RT-PCR. Serum antibody levels were assessed by means of ELISA.

Results: Here we show that FLG is regulated by the protein deacetylase SIRT1 and that SIRT1 is critical for skin barrier integrity. Epidermis-specific SIRT1 ablation causes AD-like skin lesions in mice, and mice with epidermal SIRT1 deletion are sensitive to percutaneous challenge by the protein allergen ovalbumin. In normal human keratinocytes and mouse skin SIRT1 knockdown or genetic deletion downregulates FLG, and regulation of FLG expression by SIRT1 requires the deacetylase activity of SIRT1. SIRT1 also promotes activation of the aryl hydrocarbon receptor, and the aryl hydrocarbon receptor ligand restores FLG expression in SIRT1-inhibited cells. Compared with normal human skin, SIRT1 is downregulated in both AD and non-AD lesions.

Conclusion: Our findings demonstrate a critical role of SIRT1 in skin barrier maintenance, open up new opportunities to use SIRT1 as a pharmacologic target, and might facilitate the development of mechanism-based agents for AD prevention and therapy.

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References

Guarente L . Sir2 links chromatin silencing, metabolism, and aging. Genes Dev. 2000; 14(9):1021-6. View

Howell M, Kim B, Gao P, Grant A, Boguniewicz M, DeBenedetto A . Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol. 2007; 120(1):150-5. PMC: 2669594. DOI: 10.1016/j.jaci.2007.04.031. View

Schug T, Xu Q, Gao H, Peres-Da-Silva A, Draper D, Fessler M . Myeloid deletion of SIRT1 induces inflammatory signaling in response to environmental stress. Mol Cell Biol. 2010; 30(19):4712-21. PMC: 2950528. DOI: 10.1128/MCB.00657-10. View

Kawasaki H, Nagao K, Kubo A, Hata T, Shimizu A, Mizuno H . Altered stratum corneum barrier and enhanced percutaneous immune responses in filaggrin-null mice. J Allergy Clin Immunol. 2012; 129(6):1538-46.e6. DOI: 10.1016/j.jaci.2012.01.068. View

Haigis M, Guarente L . Mammalian sirtuins--emerging roles in physiology, aging, and calorie restriction. Genes Dev. 2006; 20(21):2913-21. DOI: 10.1101/gad.1467506. View

Morar N, Cookson W, Harper J, Moffatt M . Filaggrin mutations in children with severe atopic dermatitis. J Invest Dermatol. 2007; 127(7):1667-72. DOI: 10.1038/sj.jid.5700739. View

Ong P, Ohtake T, Brandt C, Strickland I, Boguniewicz M, Ganz T . Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med. 2002; 347(15):1151-60. DOI: 10.1056/NEJMoa021481. View

Elias P, Schmuth M . Abnormal skin barrier in the etiopathogenesis of atopic dermatitis. Curr Opin Allergy Clin Immunol. 2009; 9(5):437-46. PMC: 2852024. DOI: 10.1097/ACI.0b013e32832e7d36. View

Michan S, Sinclair D . Sirtuins in mammals: insights into their biological function. Biochem J. 2007; 404(1):1-13. PMC: 2753453. DOI: 10.1042/BJ20070140. View

10.

Burbach K, Poland A, Bradfield C . Cloning of the Ah-receptor cDNA reveals a distinctive ligand-activated transcription factor. Proc Natl Acad Sci U S A. 1992; 89(17):8185-9. PMC: 49882. DOI: 10.1073/pnas.89.17.8185. View

11.

van den Bogaard E, Bergboer J, Vonk-Bergers M, van Vlijmen-Willems I, Hato S, van der Valk P . Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis. J Clin Invest. 2013; 123(2):917-27. PMC: 3561798. DOI: 10.1172/JCI65642. View

12.

Kim B, Howell M, Guttman-Yassky E, Guttman E, Gilleaudeau P, Cardinale I . TNF-α downregulates filaggrin and loricrin through c-Jun N-terminal kinase: role for TNF-α antagonists to improve skin barrier. J Invest Dermatol. 2011; 131(6):1272-9. PMC: 8609659. DOI: 10.1038/jid.2011.24. View

13.

Ming M, Feng L, Shea C, Soltani K, Zhao B, Han W . PTEN positively regulates UVB-induced DNA damage repair. Cancer Res. 2011; 71(15):5287-95. PMC: 3148338. DOI: 10.1158/0008-5472.CAN-10-4614. View

14.

Blander G, Bhimavarapu A, Mammone T, Maes D, Elliston K, Reich C . SIRT1 promotes differentiation of normal human keratinocytes. J Invest Dermatol. 2008; 129(1):41-9. PMC: 3526938. DOI: 10.1038/jid.2008.179. View

15.

Howell M, Gallo R, Boguniewicz M, Jones J, Wong C, Streib J . Cytokine milieu of atopic dermatitis skin subverts the innate immune response to vaccinia virus. Immunity. 2006; 24(3):341-8. DOI: 10.1016/j.immuni.2006.02.006. View

16.

Haigis M, Sinclair D . Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol. 2010; 5:253-95. PMC: 2866163. DOI: 10.1146/annurev.pathol.4.110807.092250. View

17.

Dajee M, Muchamuel T, Schryver B, Oo A, Alleman-Sposeto J, De Vry C . Blockade of experimental atopic dermatitis via topical NF-kappaB decoy oligonucleotide. J Invest Dermatol. 2006; 126(8):1792-803. DOI: 10.1038/sj.jid.5700307. View

18.

Blander G, Guarente L . The Sir2 family of protein deacetylases. Annu Rev Biochem. 2004; 73:417-35. DOI: 10.1146/annurev.biochem.73.011303.073651. View

19.

Williams H, Flohr C . How epidemiology has challenged 3 prevailing concepts about atopic dermatitis. J Allergy Clin Immunol. 2006; 118(1):209-13. DOI: 10.1016/j.jaci.2006.04.043. View

20.

Ichikawa T, Hayashi R, Suzuki K, Imanishi S, Kambara K, Okazawa S . Sirtuin 1 activator SRT1720 suppresses inflammation in an ovalbumin-induced mouse model of asthma. Respirology. 2012; 18(2):332-9. DOI: 10.1111/j.1440-1843.2012.02284.x. View