Authors

Nanae Nagata†, Yuta Hamasaki†, Shinichiro Inagaki†, Tatsuro Nakamura†, Daiki Horikami, Kiwako Yamamoto-Hanada, Yusuke Inuzuka, Tatsuo Shimosawa, Koji Kobayashi, Masami Narita, Yukihiro Ohya*, and Takahisa Murata*

Abstract

Atopic dermatitis (AD) is the most common inflammatory skin disease in children. The serum level of thymus and activation-regulated chemokine (TARC) is a useful AD index to reflect disease severity; however, it requires blood collection from young children. In comparison, urine samples are easier to collect in a pediatric clinical setting. Here, we analyzed the lipids excreted in urine to identify a diagnostic biomarker for AD. We generated a murine dermatitis model by repeated topical application of 2,4-dinitrofluorobenzene (DNFB) or tape-stripping the dorsal skin. Lipid metabolites excreted in the urine were comprehensively analyzed using liquid chromatography-tandem mass spectrometry. To corroborate our findings, we also analyzed urine samples from patients with AD. DNFB application induced AD-like skin lesions, including epidermal thickening, infiltration of eosinophils and T cells, and an increase in Th2 cytokine levels. Assessment of lipids excreted in urine showed a dominance of prostaglandins (PGs), namely, a PGF2α metabolite (13,14-dihydro-15-keto-tetranor-PGF1α), a PGE2 metabolite (13,14-dihydro-15-keto-tetranor-PGE2), and a PGD2 metabolite (13,14-dihydro-15-keto PGJ2). mRNA and protein expression of PGF2α, PGE2, and PGD2 synthase was upregulated in DNFB-treated skin. The tape-stripping model also caused dermatitis but without Th2 inflammation; urine PGF2α and PGD2 metabolite levels remained unaffected. Finally, we confirmed that the urinary levels of the aforementioned PG metabolites, as well as PGI2 metabolite, 6,15-diketo-13,14-dihydro-PGF1α and arachidonic acid metabolite, 17-hydroxyeicosatetraenoic acid (17-HETE) increased in patients with AD. Our data highlights the unique urinary lipid profile in patients with AD, which may provide insight into novel urinary biomarkers for AD diagnosis.

Paper Information

Journal
: The FASEB Journal
DOI
: http://dx.doi.org/10.1096/fj.202100828R
: https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202100828R