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Defects of filaggrin-like proteins in both lesional and nonlesional atopic skin.
J Allergy Clin Immunol. 2013 Apr; 131(4):1094-102.JA

Abstract

BACKGROUND

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by a disturbed epidermal barrier. In a subset of patients, this is explained by nonsense mutations in the gene encoding filaggrin (FLG).

OBJECTIVES

We sought to evaluate the respective role of FLG mutations and proinflammatory cytokines and to assess the expression of FLG, hornerin (HRNR), and FLG2, 2 FLG-like proteins, which are involved in epidermal barrier functions, in normal skin and both lesional and nonlesional skin of patients with AD.

METHODS

An FLG-genotyped cohort of 73 adults with AD and 73 aged-matched control subjects was analyzed by using immunohistochemistry and immunoblotting. Normal primary human keratinocytes were differentiated in either the absence or presence of IL-4, IL-13, and IL-25.

RESULTS

Compared with control subjects, FLG, HRNR, and FLG2 were detected at significantly lower levels in the skin of patients with AD, irrespective of their FLG genotype. The reduction was greater in lesional compared with nonlesional skin. In addition, the proFLG/FLG ratio was found to be higher in the skin of wild-type patients than in control subjects. Cytokine treatment of keratinocytes induced a dramatic reduction in FLG, FLG2, and HRNR expression both at the mRNA and protein levels.

CONCLUSION

The stratum corneum of lesional but also clinically unaffected skin of adults with AD is abnormal, with reduced expression of FLG and FLG-like proteins. In addition to nonsense mutations, proinflammatory cytokines and some defects in the proFLG processing can contribute to the FLG downregulation. Our study suggests that skin inflammation reduces the expression of FLG-like proteins, contributing to the AD-related epidermal barrier dysfunction.

Authors+Show Affiliations

UMR5165 CNRS, U1056 INSERM, University of Toulouse, Department of Dermatology, University Hospital of Toulouse, Toulouse, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo 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, Non-U.S. Gov't

Language

eng

PubMed ID

23403047

Citation

Pellerin, Laurence, et al. "Defects of Filaggrin-like Proteins in Both Lesional and Nonlesional Atopic Skin." The Journal of Allergy and Clinical Immunology, vol. 131, no. 4, 2013, pp. 1094-102.
Pellerin L, Henry J, Hsu CY, et al. Defects of filaggrin-like proteins in both lesional and nonlesional atopic skin. J Allergy Clin Immunol. 2013;131(4):1094-102.
Pellerin, L., Henry, J., Hsu, C. Y., Balica, S., Jean-Decoster, C., Méchin, M. C., Hansmann, B., Rodriguez, E., Weindinger, S., Schmitt, A. M., Serre, G., Paul, C., & Simon, M. (2013). Defects of filaggrin-like proteins in both lesional and nonlesional atopic skin. The Journal of Allergy and Clinical Immunology, 131(4), 1094-102. https://doi.org/10.1016/j.jaci.2012.12.1566
Pellerin L, et al. Defects of Filaggrin-like Proteins in Both Lesional and Nonlesional Atopic Skin. J Allergy Clin Immunol. 2013;131(4):1094-102. PubMed PMID: 23403047.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Defects of filaggrin-like proteins in both lesional and nonlesional atopic skin. AU - Pellerin,Laurence, AU - Henry,Julie, AU - Hsu,Chiung-Yueh, AU - Balica,Stéfana, AU - Jean-Decoster,Catherine, AU - Méchin,Marie-Claire, AU - Hansmann,Britta, AU - Rodriguez,Elke, AU - Weindinger,Stefan, AU - Schmitt,Anne-Marie, AU - Serre,Guy, AU - Paul,Carle, AU - Simon,Michel, Y1 - 2013/02/10/ PY - 2012/08/06/received PY - 2012/12/20/revised PY - 2012/12/26/accepted PY - 2013/2/14/entrez PY - 2013/2/14/pubmed PY - 2013/7/5/medline SP - 1094 EP - 102 JF - The Journal of allergy and clinical immunology JO - J. Allergy Clin. Immunol. VL - 131 IS - 4 N2 - BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by a disturbed epidermal barrier. In a subset of patients, this is explained by nonsense mutations in the gene encoding filaggrin (FLG). OBJECTIVES: We sought to evaluate the respective role of FLG mutations and proinflammatory cytokines and to assess the expression of FLG, hornerin (HRNR), and FLG2, 2 FLG-like proteins, which are involved in epidermal barrier functions, in normal skin and both lesional and nonlesional skin of patients with AD. METHODS: An FLG-genotyped cohort of 73 adults with AD and 73 aged-matched control subjects was analyzed by using immunohistochemistry and immunoblotting. Normal primary human keratinocytes were differentiated in either the absence or presence of IL-4, IL-13, and IL-25. RESULTS: Compared with control subjects, FLG, HRNR, and FLG2 were detected at significantly lower levels in the skin of patients with AD, irrespective of their FLG genotype. The reduction was greater in lesional compared with nonlesional skin. In addition, the proFLG/FLG ratio was found to be higher in the skin of wild-type patients than in control subjects. Cytokine treatment of keratinocytes induced a dramatic reduction in FLG, FLG2, and HRNR expression both at the mRNA and protein levels. CONCLUSION: The stratum corneum of lesional but also clinically unaffected skin of adults with AD is abnormal, with reduced expression of FLG and FLG-like proteins. In addition to nonsense mutations, proinflammatory cytokines and some defects in the proFLG processing can contribute to the FLG downregulation. Our study suggests that skin inflammation reduces the expression of FLG-like proteins, contributing to the AD-related epidermal barrier dysfunction. SN - 1097-6825 UR - https://www.unboundmedicine.com/medline/citation/23403047/Defects_of_filaggrin_like_proteins_in_both_lesional_and_nonlesional_atopic_skin_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0091-6749(13)00002-X DB - PRIME DP - Unbound Medicine ER -