SERPINB3/B4 Contributes to Early Inflammation and Barrier Dysfunction in an Experimental Murine Model of Atopic Dermatitis Umasundari Sivaprasad, Kayla.

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SERPINB3/B4 Contributes to Early Inflammation and Barrier Dysfunction in an Experimental Murine Model of Atopic Dermatitis Umasundari Sivaprasad, Kayla G. Kinker, Mark B. Ericksen, Mark Lindsey, Aaron M. Gibson, Stacey A. Bass, Nicolas S. Hershey, Jingyuan Deng, Mario Medvedovic, Gurjit K. Khurana Hershey Journal of Investigative Dermatology Volume 135, Issue 1, Pages 160-169 (January 2015) DOI: 10.1038/jid.2014.353 Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Serpinb3a is not required for the development of chronic atopic dermatitis (AD). (a) Schematic describing our chronic AD model. Transepidermal water loss (TEWL) measurements after the second (b) and third (c) patches. Sensitization to allergen measured by Aspergillus fumigatus extract (ASP)-specific IgG1 (d) and ASP-specific IgE (e). Production of IL-4 (f) and IL-17 (g) in supernatants of lymph node cultures of ASP-patched mice cultured with saline (SAL) or ASP for 5 days. Data shown are representative of three independent experiments (n=6–8 per group). Journal of Investigative Dermatology 2015 135, 160-169DOI: (10.1038/jid.2014.353) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Serpinb3a contributes to barrier dysfunction in early atopic dermatitis (AD). (a) Schematic describing our early AD model. Transepidermal water loss (TEWL) measurements after the second (b) and third (c) patches. (d) Scoring of AD-like phenotypes (excoriations, redness, and thickening). (e) Quantification of epidermal thickness after the third allergen patch. Data shown are representative of three independent experiments (n=6–8 per group). Journal of Investigative Dermatology 2015 135, 160-169DOI: (10.1038/jid.2014.353) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Inflammation is attenuated in the absence of Serpinb3a. Representative hematoxylin and eosin (H&E)-stained sections of patched skin (magnification × 20) from wild-type saline (WT-SAL) (a), knockout saline (KO-SAL) (b), wild-type Aspergillus fumigatus extract (WT-ASP) (c), and knockout Aspergillus fumigatus extract (KO-ASP) (d) mice. Representative CD3-stained sections of patched skin from WT-ASP (e) and KO-ASP (f) mice. Sensitization to allergen measured by total serum IgE levels (g), ASP-specific IgG1 (h), and ASP-specific IgE (i). Data shown are representative of three independent experiments. Scale bar=100 μm. Journal of Investigative Dermatology 2015 135, 160-169DOI: (10.1038/jid.2014.353) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Serpinb3a expression correlates with S100A8 expression in mouse skin. Quantitative real-time PCR for S100A8 (a) and Serpinb3a (b) normalized to HPRT for the indicated groups. Correlation plots between transepidermal water loss (TEWL) and S100A8/HPRT (c) and between Serpinb3a/HPRT and S100A8/HPRT (d). Expression of SERPINB4 (e) and S100A8 (f) in three independent clones (clone 1–3) stably transfected with shRNA targeting SERPINB3/B4 compared with a clone generated with the empty vector (control), normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH). HPRT, hypoxanthine-guanine phosphoribosyltransferase. Journal of Investigative Dermatology 2015 135, 160-169DOI: (10.1038/jid.2014.353) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Serpinb3a expression correlates with S100A8 expression in human subjects with atopic dermatitis (AD). Expression of (a) SERPINB3 (probe 209719:x:at), (b) SERPINB4 (probe 211906:s:at), or both (c) SERPINB3/B4 (probe 210413:x:at) and (d) S100A8 (probe 202917:s:at) in the skin of subjects with AD (AD) and normal control skin (normal) derived from GSE16161 expression array data (Guttman-Yassky et al., 2009). Correlation plots between SERPINB3 and S100A8 (e), SERPINB4 and S100A8 (f), and SERPINB3/B4 and S100A8 (g). Journal of Investigative Dermatology 2015 135, 160-169DOI: (10.1038/jid.2014.353) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Primary network of Aspergillus fumigatus extract (ASP)-affected genes generated by Ingenuity Pathway analysis (IPA). A list of differentially expressed genes (⩾2.5-fold up- or downregulated) when comparing ASP-patched with saline (SAL)-patched mice was generated for wild-type (WT) mice (a) and Serpinb3a knockout (KO) mice (b) separately. Each list of genes was submitted independently subjected to IPA to identify the top networks affected in the WT and Serpinb3a KO mice. Genes marked in red were upregulated, whereas genes in blue were downregulated in the ASP-patched mice when compared with SAL-patched mice. Journal of Investigative Dermatology 2015 135, 160-169DOI: (10.1038/jid.2014.353) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions