Transcutaneous allergen uptake and processing and its consequences for T-cell priming in atopic dermatitis
Final Report Abstract
We have developed a skin barrier-impaired mouse model in which the two structural proteins filaggrin (Flg) and hornerin (Hrnr) have been deleted. Flg and Hrnr share functional and structural features and mutations in both genes are associated with an increased risk to develop atopic diseases, e.g. atopic dermatitis. Although clinical and epidemiological studies have implicated skin barrier genes in allergological pathways, the mechanistic basis of this connection is only partially understood. The fine-tuning of the susceptibility to contact allergy is not fully understood. Skin barrier defects may facilitate cutaneous sensitization due to increased allergen-penetration. In this respect, our mouse model reflects the situation in humans, and is superior to other models with barrier-impairment. The major results and achievements of our work are as follows: 1. Generation of filaggrin/hornerin-double-knockout (FlgHrnr-/-) mice. 2. FlgHrnr-/- mice develop a transient flaky phenotype at young ages, but otherwise no overt skin phenotype at adulthood. A subclinical barrier defect was detectable on the molecular level. 3. This contributed to contact allergy development and cutaneous inflammatory processes in general. In detail, low concentrations of haptens sufficed to activate the complex immune cascade in FlgHrnr-/- mice. Our work highlights the contribution of skin barrier impairment in allergic sensitization prior to overt symptoms, and carries implications for individuals at risk, e.g. in occupational settings. Together, despite of an apparently functional skin barrier under basal conditions, FlgHrnrdeficient mice are predisposed to mount increased cutaneous inflammatory reaction. This immune dysregulation might account not only for inflammatory skin diseases, but also influences the development of eczema-associated asthma and allergies.
Publications
- (2020) Filaggrin Expression and Processing Deficiencies Impair Corneocyte Surface Texture and Stiffness in Mice. The Journal of investigative dermatology 140 (3) 615-623.e5
Thyssen, Jacob P.; Jakasa, Ivone; Riethmüller, Christoph; Schön, Michael P.; Braun, Andrea; Haftek, Marek; Fallon, Padraic G.; Wróblewski, Jacek; Jakubowski, Hieronim; Eckhart, Leopold; Declercq, Wim; Koppes, Sjors; Engebretsen, Kristiane A.; Bonefeld, Ch
(See online at https://doi.org/10.1016/j.jid.2019.07.716) - Immunostimulatory activity of murine keratinocyte-derived exosomes. 42nd Annual ESDR Meeting, 2012, Venice, Italy
Kotzerke K, Aung T, Wulf GG, Urlaub H, Schön MP, Mempel M, Braun A
- Immunostimulatory activity of murine keratinocyte-derived exosomes. Exp Dermatol. 2013: Oct; 22(10): 650-655
Kotzerke K, Mempel M, Aung T, Wulf GG, Urlaub H, Wenzel D, Schön MP, Braun A
(See online at https://doi.org/10.1111/exd.12230) - Normal steady-state, but increased cutaneous immune responses in barrier-disrupted filaggrin/hornerin (FLG/HRNR)-deficient mice. 42nd Annual Meeting of the ADF, 2015, Ulm, Germany
Rahrig S, Peterson JM, Brauns B, Lorenz V, Buhl T, Weidinger S, Mempel M, Schön MP, Braun A
- Barrieredefekte in der Ekzem-Pathogenese bei Maus und Mensch. 19. Interdisziplinäre Allergologische Wintertagung Göttingen, 2016, Göttingen, Germany
Braun A.
- Cutaneous immune response in barrier-disrupted FlgHrnr-deficient mice. 6. ADF (Arbeitsgemeinschaft Dermatologische Forschung) Winter School, 2017, Umweltforschungsstation Schneefernerhaus, Zugspitze, Germany
Braun A.
- Epidermal barrier dysfunction in FlgHrnr-deficient mice promotes allergen sensitization and aggravates experimental asthma in a mouse model of MC903-induced atopic dermatitis. 44th Annual Meeting of the ADF, 2017, Göttingen, Germany
Reier K, Brauns B, Lorenz V, Buhl T, Mempel M, Schön MP, Braun A
- Transient Epidermal Barrier Deficiency and Lowered Allergic Threshold in Filaggrin-Hornerin (FlgHrnr-/-) Double-Deficient Mice Allergy. 2019: Mar 4
Rahrig S, Dettmann JM, Brauns B, Lorenz V, Buhl T, Kezic S, Elias P, Weidinger S, Mempel M, Schön MP, Braun A
(See online at https://doi.org/10.1111/all.13756)
