Major differences between human atopic dermatitis and murine models, as determined by using global transcriptomic profiling - 18/04/17
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.
Le texte complet de cet article est disponible en PDF.Key words : Atopic dermatitis, TH1, TH2, TH17, psoriasis, contact dermatitis, mouse model, NC/Nga, filaggrin, oxazolone, ovalbumin, IL-2
Abbreviations used : AD, CD, CLDN8, Ct, DEG, FCH, FDR, FLG, LOR, MADAD, OVA, OXA, TLDA
Plan
| Supported by a research grant (to E.G.-Y.) from LEO Pharma A/S. S.N., M.S.-F., and J.G.K. were supported by grant no. 5UL1RR024143-02 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and the NIH Roadmap for Medical Research. D.A.E. is partly funded by the Danish Ministry of Science and Higher Education. |
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| Disclosure of potential conflict of interest: D. A. Ewald is an employee of Leo Pharma A/S. S. Noda receives grant support from the CTSA program. N. Svitacheva is an employee of Leo Pharma A/S. T. Labuda is an employee of Leo Pharma A/S. J. G. Krueger reports grants paid to his institution and personal fees from Novartis, Pfizer, Janssen, Lilly, Merck, Kadmon, Dermira, Boehringer, BMS, and Paraxel during the conduct of the study; grants paid to his institution from Amgen, Innovaderm and Kyowa; and personal fees from Serono, BiogenIdec, Delenex, AbbVie, Sanofi, Baxter, Xenoport, and Kineta. E. Guttman-Yassky serves on the board for Sanofi Aventis, Regeneron, Stiefel/GlaxoSmithKline, MedImmune, Celgene, Anacor, and Leo Pharma; serves as a consultant for Regeneron, Sanofi Aventis, MedImmune, Celgene, Steifel/GlaxoSmithKline, Celsus, BMS, Amgen and Drais; and receives grant support from Regeneron, Celgene, BMS and Janssen. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 139 - N° 2
P. 562-571 - février 2017 Retour au numéro
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