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Keratinocyte Proline-Rich Protein Deficiency in Atopic Dermatitis Leads to Barrier Disruption  Hiraku Suga, Tomonori Oka, Makoto Sugaya, Yasunari Sato,

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Presentation on theme: "Keratinocyte Proline-Rich Protein Deficiency in Atopic Dermatitis Leads to Barrier Disruption  Hiraku Suga, Tomonori Oka, Makoto Sugaya, Yasunari Sato,"— Presentation transcript:

1 Keratinocyte Proline-Rich Protein Deficiency in Atopic Dermatitis Leads to Barrier Disruption 
Hiraku Suga, Tomonori Oka, Makoto Sugaya, Yasunari Sato, Tsuyoshi Ishii, Hiroyuki Nishida, Shumpei Ishikawa, Masashi Fukayama, Shinichi Sato  Journal of Investigative Dermatology  Volume 139, Issue 9, Pages e7 (September 2019) DOI: /j.jid Copyright © 2019 The Authors Terms and Conditions

2 Figure 1 Decreased hKPRP expression in AD lesional skin. (a) Hematoxylin and eosin staining of KPRP in normal and AD lesion. Scale bar = 50 μm. (b) hKPRP mRNA expression in healthy skin (normal) and AD lesions (n = 6–8). ∗∗P < (c) Correlation between the expression levels of hKPRP and those of FLG and LOR in the skin was measured with the Spearman rank correlation test (n = 14). AD, atopic dermatitis; h, human; HE, hematoxylin and eosin. Journal of Investigative Dermatology  , e7DOI: ( /j.jid ) Copyright © 2019 The Authors Terms and Conditions

3 Figure 2 hKPRP and loricrin are histologically colocalized while they are in different fractions within cells. (a) hKPRP mRNA expression by normal human epidermal keratinocytes incubated with IL-4, IL-13, or IFN-γ assessed by quantitative real-time reverse transcriptase–PCR (n = 4). (b, c) Immunofluorescence staining of hKPRP and (b) filaggrin or (c) loricrin with normal human skin. Scale bar = 50 μm. (d) By using highly differentiated NHEKs, FLG and hKPRP were mainly detected in the pellet extract fraction. ∗P < (e) Pull-down detection of PKP1, CTNG, and DSP. KPRP protein levels in stably transfected HaloTag vector (Cont) or HaloTag-KPRP vector (KPRP) with HaCaT cells. CE, cytoplasmic extract; CTNG, γ-catenin; DSP, desmoplakin; FLG, filaggrin; h, human; LOR, loricrin; ME, membrane extract; NE, nuclear extract; PE, pellet extract; PKP1, plakophilin 1. Journal of Investigative Dermatology  , e7DOI: ( /j.jid ) Copyright © 2019 The Authors Terms and Conditions

4 Figure 3 Decreased Lor and Flg expression in Kprp+/– mice. (a) Kprp-knockout mice generated by using the homologous recombination system. (b) The deficiency of Kprp confirmed by Western blotting analysis. Actb = β-actin. (c) Immunohistochemical staining of mice skin. Scale bar = 20 μm. (d) mRNA expression analysis of back skin (n = 5). ∗P < Flg, filaggrin; HT, heterozygous; HO, homozygous; kb, kilobase; Lor, loricrin; WT, wild type. Journal of Investigative Dermatology  , e7DOI: ( /j.jid ) Copyright © 2019 The Authors Terms and Conditions

5 Figure 4 Altered stratum corneum structure in Kprp+/– heterozygous mice skin. (a) Negative replica of postnatal day 6 mice. Scale bar = 200 μm. (b) Hematoxylin and eosin-stained skin sections. Scale bar = 20 μm. (c–f) Transmission electron microscopy analysis of epidermis. (c) Lower part of honey layer. Scale bar = 5 μm. (d) The distance from the SG1 layer to the fifth layer of corneocytes (n = 5). (e) The border between stratum corneum and stratum granulosum. Scale bar = 500 nm. Asterisk shows the corneodesmosome. (f) The gray scale ratio compared with desmosomes and keratin bundle (n = 7). (g) Immunohistochemical staining for corneodesmosin. corneodesmosin-positive cell layers are between arrowheads. Scale bar = 20 μm. (h) The width of corneodesmosin-positive cell layers (n = 9). HT, heterozygous; SC, stratum corneum; SG, stratum granulosum; WT, wild type. Journal of Investigative Dermatology  , e7DOI: ( /j.jid ) Copyright © 2019 The Authors Terms and Conditions

6 Figure 5 Enhanced percutaneous immune responses in Kprp+/– heterozygous (HT) mice. (a) Transepidermal water loss (TEWL) of back skin (n = 20–22). ∗P < (b) Ear swelling responses by applying croton oil (n = 18–19). ∗P < (c) Ear swelling responses after epicutaneous application of oxazolone (OXA) on day 7 (n = 12). ∗∗P < (d) Repeated application of OXA for 21 days (n = 12). ∗P < (e) Histology after application of OXA on day 21. (f) Ovalbumin (OVA)-specific IgE level in blood by repeated epicutaneous application on day 29 (n = 9). ∗P < hrs, hours; HT, heterozygous; WT, wild type. Journal of Investigative Dermatology  , e7DOI: ( /j.jid ) Copyright © 2019 The Authors Terms and Conditions

7 Supplementary Figure S1
SNP rs polymorphism in human KPRP associated with atopic dermatitis severity. (a) Copy number variation analysis of human KPRP with nonpolymorphic probes. (b) Single nucleotide rs polymorphism in human KPRP with atopic dermatitis severity. Journal of Investigative Dermatology  , e7DOI: ( /j.jid ) Copyright © 2019 The Authors Terms and Conditions

8 Supplementary Figure S2
Decreased filaggrin and loricrin expression by normal human epidermal keratinocytes stimulated with inflammatory cytokines. (a, b) Filaggrin and loricrin mRNA levels in normal human epidermal keratinocytes incubated with IL-4, IL-13, or IFN-γ assessed by quantitative real-time reverse transcriptase–PCR (n = 4). ∗P < 0.05. Journal of Investigative Dermatology  , e7DOI: ( /j.jid ) Copyright © 2019 The Authors Terms and Conditions

9 Supplementary Figure S3
No obvious difference in KPRP–/– (HO)-knockout mice under SPF conditions. (a) Knockout strategy for KPRP–/– (HO) mice. (b, c) To confirm the successful recombination, Southern blot analyses and genotyping PCR with genomic DNA were performed. (d) Phenotypes of 8- to 12-week-old WT and KPRP–/– (HO) mice under SPF conditions. bp, base pair; HO, homozygous; HT, heterozygous; kb, kilobase; Kbp, kilo base pair; M, marker; SPF, specific pathogen-free; WT, wild type. Journal of Investigative Dermatology  , e7DOI: ( /j.jid ) Copyright © 2019 The Authors Terms and Conditions

10 Supplementary Figure S4
Comparisons of Kprp–/– (HO), Kprp+/– (HT), and WT mice. (a) Transepidermal water loss of back skin (n = 20–22). (b) Ear swelling responses by applying croton oil (n = 18–19). ∗P < (c) Ear swelling responses after epicutaneous application of oxazolone on day 7 (n = 12). ∗P < 0.05. (d) Ovalbumin-specific IgE level in blood by repeated epicutaneous application on day 29 (n = 9). ∗P < (e) mRNA expression analysis of back skin (n = 4–6). ∗P < 0.05, ∗∗P < HO, homozygous; HT, heterozygous; hrs, hours; WT, wild type. Journal of Investigative Dermatology  , e7DOI: ( /j.jid ) Copyright © 2019 The Authors Terms and Conditions

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