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

Ewald, David A. ; Noda, Shinji ; Oliva, Margeaux ; Litman, Thomas ; Nakajima, Saeko ; Li, Xuan ; Xu, Hui ; Workman, Christopher T. ; Scheipers, Peter and Svitacheva, Naila LU , et al. (2017) In Journal of Allergy and Clinical Immunology 139(2). p.562-571
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
keywords
Atopic dermatitis, contact dermatitis, filaggrin, IL-2, mouse model, NC/Nga, ovalbumin, oxazolone, psoriasis, T1, T17, T2
in
Journal of Allergy and Clinical Immunology
volume
139
issue
2
pages
562 - 571
publisher
Elsevier
external identifiers
  • scopus:85006287975
  • pmid:27702671
ISSN
0091-6749
DOI
10.1016/j.jaci.2016.08.029
language
English
LU publication?
no
id
c3a165a3-ba79-4b4f-ad28-dd6291921840
date added to LUP
2020-02-26 16:20:52
date last changed
2024-06-13 13:33:36
@article{c3a165a3-ba79-4b4f-ad28-dd6291921840,
  abstract     = {{<p>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 T<sub>H</sub>1, T<sub>H</sub>2, and also T<sub>H</sub>17 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 T<sub>H</sub>1-centered reaction, and flaky tail mice demonstrate a strong T<sub>H</sub>17 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.</p>}},
  author       = {{Ewald, David A. and Noda, Shinji and Oliva, Margeaux and Litman, Thomas and Nakajima, Saeko and Li, Xuan and Xu, Hui and Workman, Christopher T. and Scheipers, Peter and Svitacheva, Naila and Labuda, Tord and Krueger, James G. and Suárez-Fariñas, Mayte and Kabashima, Kenji and Guttman-Yassky, Emma}},
  issn         = {{0091-6749}},
  keywords     = {{Atopic dermatitis; contact dermatitis; filaggrin; IL-2; mouse model; NC/Nga; ovalbumin; oxazolone; psoriasis; T1; T17; T2}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{2}},
  pages        = {{562--571}},
  publisher    = {{Elsevier}},
  series       = {{Journal of Allergy and Clinical Immunology}},
  title        = {{Major differences between human atopic dermatitis and murine models, as determined by using global transcriptomic profiling}},
  url          = {{http://dx.doi.org/10.1016/j.jaci.2016.08.029}},
  doi          = {{10.1016/j.jaci.2016.08.029}},
  volume       = {{139}},
  year         = {{2017}},
}