title: SERPINB3/B4 contributes to early inflammation and barrier dysfunction in an experimental murine model of atopic dermatitis.
abstract: Serine proteases are critical for epidermal barrier homeostasis, and their aberrant expression and/or activity is associated with chronic skin diseases. Elevated levels of the serine protease inhibitors SERPINB3 and SERPINB4 are seen in patients with atopic dermatitis and psoriasis. However, their mechanistic role in the skin is unknown. To evaluate the contribution of Serpinb3a (mouse homolog of SERPINB3 and SERPINB4) in atopic dermatitis, we examined the effect of topical Aspergillus fumigatus extract exposure in wild-type and Serpinb3a-null mice on transepidermal water loss (TEWL), sensitization, and inflammation. Allergen exposure induced Serpinb3a expression in the skin, along with increased TEWL, epidermal thickness, and skin inflammation, all of which were attenuated in the absence of Serpinb3a. Attenuated TEWL correlated with decreased expression of the pro-inflammatory marker S100A8. Silencing of SERPINB3/B4 in human keratinocytes decreased S100A8 expression, supporting a role for SERPINB3/B4 in the initiation of the acute inflammatory response. RNA-seq analysis following allergen exposure identified a network of pro-inflammatory genes induced in wild-type mice that was absent in Serpinb3a-null mice. In conclusion, Serpinb3a deficiency attenuates barrier dysfunction and the early inflammatory response following cutaneous allergen exposure, supporting a role for Serpinb3a (mice) and SERPINB3/B4 (humans) early in atopic dermatitis.
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Umasundari
authors.initials: U
authors.lastname: Sivaprasad
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Kayla G
authors.initials: KG
authors.lastname: Kinker
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Mark B
authors.initials: MB
authors.lastname: Ericksen
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Lindsey
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Gibson
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Stacey A
authors.initials: SA
authors.lastname: Bass
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Nicolas S
authors.initials: NS
authors.lastname: Hershey
authors.affiliation: Department of Environmental Health, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Deng
authors.affiliation: Department of Environmental Health, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Medvedovic
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA. Electronic address: Gurjit.Hershey@cchmc.org.
authors.forename: Gurjit K
authors.initials: GK
authors.lastname: Khurana Hershey
mesh_terms: D000208:Acute Disease; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001232:Aspergillus fumigatus / Q000276:immunology; D040501:Calgranulin A / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002908:Chronic Disease; D003876:Dermatitis, Atopic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D004817:Epidermis / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D015603:Keratinocytes / Q000276:immunology / Q000378:metabolism; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D015843:Serpins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014870:Water Loss, Insensible / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D040501:Calgranulin A; C086145:S100a8 protein, mouse; C495969:Serpinb3b protein, mouse; D015843:Serpins; C051072:squamous cell carcinoma-related antigen
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