Altered stratum corneum barrier and enhanced percutaneous immune responses in filaggrin-null mice
Abstract
Background Loss-of-function mutations in filaggrin are major predisposing factors for atopic dermatitis. Although various reports suggest a critical role for filaggrin in stratum corneum (SC) barrier formation, the lack of filaggrin-null (Flg(-/-)) mice has hampered detailed in vivo analysis of filaggrin's functions. Objective We sought to generate Flg(-/-) mice and to assess the effect of filaggrin loss on SC barrier function and percutaneous immune responses. Methods We generated Flg(-/-) mice using gene targeting and assessed the morphology, hydration, mechanical strength, and antigen permeability of their SC. Percutaneous immune responses were evaluated through irritant- and hapten-induced contact hypersensitivity studies and by measuring humoral responses to epicutaneous sensitization with protein antigen. Results Newborn Flg(-/-) mice exhibited dry scaly skin. Despite marked decreases in natural moisturizing factor levels, which are filaggrin degradation products, SC hydration and transepidermal water loss were normal. Microscopic analyses suggested premature shedding of SC layers, and indeed, increased desquamation under mechanical stress was demonstrated. Loss of keratin patterns, which are critical for corneocyte stabilization, is likely attributable to fragility in the Flg(-/-) SC. Antigens penetrated the Flg(-/-) SC more efficiently, leading to enhanced responses in hapten-induced contact hypersensitivity and higher serum levels of anti-ovalbumin IgG(1) and IgE. Co…
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Flg-deficient mice exhibit reduced epidermal barrier function with enhanced susceptibility to environmental sensitization.
“Flg-deficient mice exhibit reduced epidermal barrier function with enhanced susceptibility to environmental sensitization [31]”
From Antioxidant Artemisia princeps Extract Enhances the Expression of Filaggrin and Loricrin via the AHR/OVOL1 Pathway (2017) · cites this paper as [31]
Cites
Moisturization and skin barrier function
Rawlings, A. V., & Harding, C. R. (2004) · Dermatologic Therapy · doi:10.1111/j.1396-0296.2004.04s1005.x · Cited by 924 · see citing works
Weerheim, A., & Ponec, M. (2001) · Archives of Dermatological Research · doi:10.1007/s004030100212 · Cited by 302 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Weidinger, S., & Novak, N. (2016) · The Lancet · doi:10.1016/s0140-6736(15)00149-x · Cited by 1,908 · see citing works
Weidinger, S., Beck, L. A., Bieber, T., Kabashima, K., & Irvine, A. D. (2018) · Nature Reviews Disease Primers · doi:10.1038/s41572-018-0001-z · Cited by 1,549 · see citing works
Application of moisturizer to neonates prevents development of atopic dermatitis
Horimukai, K., Morita, K., Narita, M., Kondo, M., Kitazawa, H., Nozaki, M., Shigematsu, Y., Yoshida, K., Niizeki, H., Motomura, K.-I., et al. (2014) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2014.07.060 · Cited by 607 · see citing works
Self-citationLangerhans cells - the macrophage in dendritic cell clothing
Doebel, T., Voisin, B., & Nagao, K. (2017) · Trends in Immunology · doi:10.1016/j.it.2017.06.008 · Cited by 270 · see citing works
Self-citationEgawa, G., & Kabashima, K. (2016) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2016.06.002 · Cited by 265 · see citing works
Amano, W., Nakajima, S., Kunugi, H., Numata, Y., Kitoh, A., Egawa, G., Dainichi, T., Honda, T., Otsuka, A., Kimoto, Y., et al. (2015) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2015.03.051 · Cited by 259 · see citing works
Skin barrier defects in atopic dermatitis
Agrawal, R., & Woodfolk, J. A. (2014) · Current Allergy and Asthma Reports · doi:10.1007/s11882-014-0433-9 · Cited by 201 · see citing works
Rerknimitr, P., Otsuka, A., Nakashima, C., & Kabashima, K. (2017) · Inflammation and Regeneration · doi:10.1186/s41232-017-0044-7 · Cited by 187 · see citing works
Saunders, S. P., Moran, T., Floudas, A., Wurlod, F., Kaszlikowska, A., Salimi, M., Quinn, E. M., Oliphant, C. J., Núñez, G., McManus, R., et al. (2016) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2015.06.045 · Cited by 160 · see citing works
Pan, T.-L., Wang, P.-W., Aljuffali, I. A., Huang, C.-T., Lee, C.-W., & Fang, J.-Y. (2015) · Journal of Dermatological Science · doi:10.1016/j.jdermsci.2015.01.011 · Cited by 158 · see citing works
Skin barrier in atopic dermatitis
Kezic, S. (2014) · Frontiers in Bioscience · doi:10.2741/4225 · Cited by 115 · see citing works
Protease-activated receptors in health and disease
Peach, C. J., Edgington-Mitchell, L. E., Bunnett, N. W., & Schmidt, B. L. (2023) · Physiological Reviews · doi:10.1152/physrev.00044.2021 · Cited by 116 · see citing works
Archer, N. K., Jo, J.-H., Lee, S. K., Kim, D., Smith, B., Ortines, R. V., Wang, Y., Marchitto, M. C., Ravipati, A., Cai, S. S., et al. (2019) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2018.08.042 · Cited by 82 · see citing works
Hou, M., Sun, R., Hupe, M., Kim, P. L., Park, K., Crumrine, D., Lin, T., Santiago, J. L., Mauro, T. M., Elias, P. M., et al. (2013) · Experimental Dermatology · doi:10.1111/exd.12102 · Cited by 66 · see citing works
Hirano, A., Goto, M., Mitsui, T., Hashimoto-Hachiya, A., Tsuji, G., & Furue, M. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18091948 · Cited by 48 · see citing works
Cutaneous Immune Cell-Microbiota Interactions Are Controlled by Epidermal JunB/AP-1
Uluçkan, Ö., Jiménez, M., Roediger, B., Schnabl, J., Díez-Córdova, L. T., Troulé, K., Weninger, W., & Wagner, E. F. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.09.042 · Cited by 21 · see citing works
Atopic Dermatitis: The Relationship Between Immune Mediators and Skin Lipid Barrier
You, H., & Liang, Y. (2025) · Clinical Reviews in Allergy & Immunology · doi:10.1007/s12016-025-09057-y · Cited by 17 · see citing works
- Authors
- Kawasaki, H., Nagao, K., Kubo, A., Hata, T., Shimizu, A., Mizuno, H., Yamada, T., & Amagai, M.
- Affiliations
- Keio University (JP)
- RIKEN Center for Brain Science (JP)
- Corresponding author
- Amagai, Masayuki
- ORCID
- Venue
- Journal of Allergy and Clinical Immunology
- Publisher
- Elsevier BV
- Published
- 2012-06
- Volume
- 129
- Issue
- 6
- Pages
- 1538-1546.e6
- ISSN
- 0091-6749 (ISSN-L)
- OpenAlex
- W2023782615
- Cited by
- 301
- References
- 2
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 17 · 2023: 10 · 2022: 20 · 2021: 21 · 2020: 20 · 2019: 21 · 2018: 33 · 2017: 27 · 2016: 22 · 2015: 29 · 2014: 34 · 2013: 24 · 2012: 9
- FWCI
- 38.39
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Allergy and Clinical Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (23390086, 22249044, 21229014)
- Topics
- Health Sciences › Medicine › Dermatology › Dermatology and Skin Diseases
- Health Sciences › Medicine › Dermatology › Contact Dermatitis and Allergies
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advancements in Transdermal Drug Delivery
- Keywords
- filaggrin, stratum corneum barrier, atopic dermatitis, contact hypersensitivity, hapten sensitization, natural moisturizing factor, transepidermal water loss, desquamation, keratin, epicutaneous sensitization, skin hydration
- MeSH terms
- Filaggrin Proteins, Animals, Fluoresceins, Genotype, Intermediate Filament Proteins, Keratins, Permeability, Skin, Mice, Knockout, Blood-Aqueous Barrier, Epithelium, Corneal, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
