title: Pathogenesis of Diet-induced Atopic Dermatitis in Hairless Mice.
abstract: Atopic dermatitis (AD) is a common pruritic chronic skin disease. AD pathogenesis remains elusive, but may involve complex interplays among skin barrier dysfunction, Th2 inflammation, and pruritus. Current treatments for AD are still limited to symptomatic therapies. We previously showed that HR-1 hairless mice fed a special diet (HR-AD) develop AD-like symptoms; however, the ingredient(s) causing dermatitis remain unclear. In this study, we examined whether the deficiency of certain polyunsaturated fatty acids (PUFAs) was involved in the diet-induced AD pathogenesis. In the serum of HR-AD-fed mice, levels of linoleic acid (LA, 18:2n-6) and α-linolenic acid (ALA, 18:3n-3), as well as their metabolites, were markedly decreased. HR-AD-induced AD symptoms were significantly ameliorated by LA supplementation, and to a lesser extent by ALA supplementation. In addition, LA metabolites, such as γ-linolenic acid and arachidonic acid, had effects similar to those of LA. Further, using semi-purified custom diets, we attempted to reproduce HR-AD-induced AD symptoms. Unexpectedly, a deficiency in unsaturated fatty acids (UFAs) alone caused mild symptoms. However, several modifications of fat and carbohydrate components in the diet revealed that dietary deficiencies of UFA and cornstarch were required to fully induce severe AD symptoms. Furthermore, we examined the influence of genetic background on the development of diet-induced AD and found that a hypomorphic mutation in the hairless gene Hr, encoding a nuclear receptor (NR) corepressor, was essential for the complete development of diet-induced pruritic atopic skin. Thus, our findings suggest that certain PUFAs and NRs are new, potential therapeutic targets for treating AD.
authors.affiliation: Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University.
authors.forename: Masanori
authors.initials: M
authors.lastname: Fujii
mesh_terms: D000818:Animals; D056970:Co-Repressor Proteins / Q000235:genetics; D003876:Dermatitis, Atopic / Q000209:etiology* / Q000235:genetics / Q000628:therapy; D004032:Diet / Q000009:adverse effects*; D004195:Disease Models, Animal; D005231:Fatty Acids, Unsaturated / Q000172:deficiency; D006801:Humans; D019787:Linoleic Acid / Q000008:administration & dosage / Q000097:blood / Q000172:deficiency*; D008812:Mice, Hairless; D058990:Molecular Targeted Therapy; D009154:Mutation; D013213:Starch / Q000009:adverse effects; D014157:Transcription Factors / Q000235:genetics
chemical_list: D056970:Co-Repressor Proteins; D005231:Fatty Acids, Unsaturated; D014157:Transcription Factors; C088661:hr protein, mouse; D013213:Starch; D019787:Linoleic Acid