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Altered stratum corneum barrier and enhanced percutaneous immune responses in filaggrin-null mice  Hiroshi Kawasaki, MD, Keisuke Nagao, MD, PhD, Akiharu.

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Presentation on theme: "Altered stratum corneum barrier and enhanced percutaneous immune responses in filaggrin-null mice  Hiroshi Kawasaki, MD, Keisuke Nagao, MD, PhD, Akiharu."— Presentation transcript:

1 Altered stratum corneum barrier and enhanced percutaneous immune responses in filaggrin-null mice 
Hiroshi Kawasaki, MD, Keisuke Nagao, MD, PhD, Akiharu Kubo, MD, PhD, Tsuyoshi Hata, PhD, Atsushi Shimizu, DVM, PhD, Hideaki Mizuno, PhD, Taketo Yamada, MD, PhD, Masayuki Amagai, MD, PhD  Journal of Allergy and Clinical Immunology  Volume 129, Issue 6, Pages e6 (June 2012) DOI: /j.jaci Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 Loss of filaggrin expression in Flg−/− mice. A, Western blot analysis of urea/Tris extracts from wild-type (+/+), heterozygous (+/−), and Flg−/− (−/−) mice and 5-day-old ft/ma littermates. Left, Molecular weight marker sizes (in kilodaltons). B, Immunohistochemical staining of wild-type, Flg−/−, and ft/ma dorsal skin on day 4. FG, Filaggrin; ft PFG, ft/ma mutant profilaggrin; INV, involucrin; K1, keratin 1; LOR, loricrin; PFG, profilaggrin. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 Flg−/− mice exhibit an ichthyotic skin phenotype. A-C, Macroscopic (Fig 2, A), negative replica (Fig 2, B), and histologic (hematoxylin and eosin staining; Fig 2, C) images of neonatal Flg−/− mice. Insets, Higher-magnification images of the highlighted areas. Arrows, Keratohyalin granules. D and E, Macroscopic (upper panel) and histologic (lower panel) images of tail skin from wild-type (+/+) and Flg−/− (−/−) mice on days 4 (Fig 2, D) and 13 (Fig 2, E). Arrowheads, Scale. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 Decreased in vivo NMF levels and normal water content and TEWL in Flg−/− SC. A, Free amino acid content in the SC of neonatal wild-type (+/+) and Flg−/− (−/−) mice. B and C, Dorsal skin NMF concentration (Fig 3, B) and relative water profiles (Fig 3, C) were measured in vivo by using confocal Raman microspectroscopy. D-F, Comparison of TEWL (Fig 3, D), SC hydration (Fig 3, E), and SC surface pH (Fig 3, F) between neonatal and adult wild-type, heterozygous (+/−), and Flg−/− mice. NS, Not significant. ∗P < .05, ∗∗P < .01, and ∗∗∗P < .001. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 Filaggrin-deficient SC is fragile and more susceptible to TS. A, Low-vacuum scanning electron microscopic images of paws (upper panel) and abdominal skin (lower panel). B, Histologic images of the SC layers. C and D, Evaluation of SC fragility by using TS. Arrows, Cornified materials; arrowheads, nuclei of cells in viable layers. +/+, Wild-type mice; −/−, Flg−/− mice. ∗P < .05 and ∗∗P < .01. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig 5 Abnormal keratin filament aggregation in Flg−/− epidermis. A, Disorganized keratohyaline granules (KG) and immature bundles of keratin filaments (arrowheads) in Flg−/− SG. Asterisks, Desmosome. B, Disturbed keratin intermediate filament organization in Flg−/− SC. Lower panels, Higher-magnification images of the highlighted areas. C and D, Lamellar body secretion (arrowheads), corneodesmosomes (arrows; Fig 5, C), and extracellular lamellar bilayers (Fig 5, D) at the SG-SC interface appeared normal in Flg−/− (−/−) mice. +/+, Wild-type mice. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig 6 Increased penetration of foreign materials in Flg−/− mice. A and C, Calcein solution (Fig 6, A) and calcein encapsulated in liposomes (Fig 6, C) were topically applied to the tails of 8-week-old mice, and permeability was examined with confocal microscopy. B and D, Penetration ratio: the proportion of fluorescence that penetrated more than half of the SC. Dashed white lines, Border between the SC and SG. +/+, Wild-type mice; −/−, Flg−/− mice; NS, not significant. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Fig 7 Enhanced percutaneous immune responses in Flg−/− mice. A and B, Percentage increase in ear thickness of mice after topical application of croton oil (Fig 7, A) and after DNFB challenge with (+) or without (−) sensitization (Fig 7, B). C, Histology after DNFB challenge. D, Systemic immune responses to repeated percutaneous application of OVA. OVA-specific serum IgG1 and IgE levels were measured by using ELISA. +/+, Wild-type mice; −/−, Flg−/− mice. ∗P < .05 and ∗∗P < .01. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 Fig E1 A, Partial restriction enzyme maps and schematic representation of the strategy used to ablate Flg expression in mice. B and C, Southern blot analyses with BamHI-digested (Fig E1, B) and MscI-digested (Fig E1, C) genomic DNA were performed to confirm the successful recombination at the sides of the long (Fig E1, B) and short (Fig E1, C) homology arms, respectively. WT, Wild-type. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

10 Fig E2 Clinical photographs of 12- to 15-week-old wild-type (+/+), Flg−/− (−/−), and ft/ma mice under SPF conditions. Whereas ft/ma mice had dermatitis (arrows) spontaneously, Flg−/− mice did not have any cutaneous manifestation. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

11 Fig E3 Comparison of TEWL (A) and SC hydration (B) between P4 and P5 and 12- to 14-week-old wild-type (+/+), Flg−/− (−/−), and ft/ma mice in a steady state under normal unmanipulated housing conditions. At 12 to 14 weeks, the ft/ma mice used in this study had spontaneous dermatitis. ∗P < .05 and ∗∗P < .01. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

12 Fig E4 Comparison of SC lipid contents between neonatal wild-type (+/+) and Flg−/− (−/−) mice. A and B, Dorsal skin ceramide 3 (Fig E4, A) and cholesterol (Fig E4, B) profiles were measured by using in vivo confocal Raman microspectroscopy. C, Analysis of lipid extracts isolated from SC sheets. FFA, Free fatty acids; NS, not significant. ∗P < .05 and ∗∗P < .01. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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