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J Allergy Clin Immunol. 2017 Feb;139(2):562-571. doi: 10.1016/j.jaci.2016.08.029. Epub 2016 Oct 1.

Major differences between human atopic dermatitis and murine models, as determined by using global transcriptomic profiling.

Author information

1
Laboratory for Investigative Dermatology, Rockefeller University, New York, NY; Exploratory Biology, LEO Pharma A/S, Ballerup, Denmark; Regulatory Genomics, Integrative Systems Biology, Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kgs. Lyngby, Denmark.
2
Laboratory for Investigative Dermatology, Rockefeller University, New York, NY.
3
Department of Dermatology and the Laboratory for Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, NY.
4
Exploratory Biology, LEO Pharma A/S, Ballerup, Denmark; Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
5
Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
6
Regulatory Genomics, Integrative Systems Biology, Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kgs. Lyngby, Denmark.
7
Exploratory Biology, LEO Pharma A/S, Ballerup, Denmark.
8
In Vivo Biology, LEO Pharma A/S, Ballerup, Denmark.
9
Translational Medicine, LEO Pharma A/S, Ballerup, Denmark.
10
Laboratory for Investigative Dermatology, Rockefeller University, New York, NY; Department of Dermatology, the Departments of Population Health Science and Policy, and the Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY.
11
Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan; Singapore Immunology Network (SIgN) and Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
12
Laboratory for Investigative Dermatology, Rockefeller University, New York, NY; Department of Dermatology and the Laboratory for Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, NY. Electronic address: Emma.Guttman@mountsinai.org.

Abstract

BACKGROUND:

Atopic dermatitis (AD) is caused by a complex interplay between immune and barrier abnormalities. Murine models of AD are essential for preclinical assessments of new treatments. Although many models have been used to simulate AD, their transcriptomic profiles are not fully understood, and a comparison of these models with the human AD transcriptomic fingerprint is lacking.

OBJECTIVE:

We sought to evaluate the transcriptomic profiles of 6 common murine models and determine how they relate to human AD skin.

METHODS:

Transcriptomic profiling was performed by using microarrays and quantitative RT-PCR on biopsy specimens from NC/Nga, flaky tail, Flg-mutated, ovalbumin-challenged, oxazolone-challenged, and IL-23-injected mice. Gene expression data of patients with AD, psoriasis, and contact dermatitis were obtained from previous patient cohorts. Criteria of a fold change of 2 or greater and a false discovery rate of 0.05 or less were used for gene arrays.

RESULTS:

IL-23-injected, NC/Nga, and oxazolone-challenged mice show the largest homology with our human meta-analysis-derived AD transcriptome (37%, 18%, 17%, respectively). Similar to human AD, robust TH1, TH2, and also TH17 activation are seen in IL-23-injected and NC/Nga mice, with similar but weaker inflammation in ovalbumin-challenged mice. Oxazolone-challenged mice show a TH1-centered reaction, and flaky tail mice demonstrate a strong TH17 polarization. Flg-mutated mice display filaggrin downregulation without significant inflammation.

CONCLUSION:

No single murine model fully captures all aspects of the AD profile; instead, each model reflects different immune or barrier disease aspects. Overall, among the 6 murine models, IL-23-injected mice best simulate human AD; still, the translational focus of the investigation should determine which model is most applicable.

KEYWORDS:

Atopic dermatitis; IL-2; NC/Nga; T(H)1; T(H)17; T(H)2; contact dermatitis; filaggrin; mouse model; ovalbumin; oxazolone; psoriasis

PMID:
27702671
DOI:
10.1016/j.jaci.2016.08.029
[Indexed for MEDLINE]

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