Mead acid inhibits retinol-induced irritant contact dermatitis via peroxisome proliferator-activated receptor alpha

Azusa Saika; Prabha Tiwari; Takahiro Nagatake; Eri Node; Koji Hosomi; Tetsuya Honda; Kenji Kabashima; Jun Kunisawa

doi:10.3389/fmolb.2023.1097955

Mead acid inhibits retinol-induced irritant contact dermatitis via peroxisome proliferator-activated receptor alpha

Front Mol Biosci. 2023 Feb 7:10:1097955. doi: 10.3389/fmolb.2023.1097955. eCollection 2023.

Authors

Azusa Saika¹, Prabha Tiwari^{1

2}, Takahiro Nagatake^{1

3}, Eri Node¹, Koji Hosomi¹, Tetsuya Honda⁴, Kenji Kabashima⁵, Jun Kunisawa^{1

6

7

8

9

10}

Affiliations

¹ Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research and Laboratory of Gut Environmental System, Collaborative Research Center for Health and Medicine, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Ibaraki, Osaka, Japan.
² Laboratory for Transcriptome Technology, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
³ Laboratory of Functional Anatomy, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Kanagawa, Japan.
⁴ Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
⁵ Department of Dermatology, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.
⁶ International Vaccine Design Center, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo, Japan.
⁷ Graduate School of Medicine, Graduate School of Dentistry, Graduate School of Pharmaceutical Sciences, Graduate School of Science, Osaka University, Suita, Osaka, Japan.
⁸ Department of Microbiology and Immunology, Graduate School of Medicine, Kobe University, Kobe, Hyogo, Japan.
⁹ Research Organization for Nano and Life Innovation, Waseda University, Shinjuku, Tokyo, Japan.
¹⁰ Graduate School of Biomedical and Health Sciences, Hiroshima University, Higashi-Hiroshima, Hiroshima, Japan.

Abstract

Retinol is widely used in topical skincare products to ameliorate skin aging and treat acne and wrinkles; however, retinol and its derivatives occasionally have adverse side effects, including the induction of irritant contact dermatitis. Previously, we reported that mead acid (5,8,11-eicosatrienoic acid), an oleic acid metabolite, ameliorated skin inflammation in dinitrofluorobenzene-induced allergic contact hypersensitivity by inhibiting neutrophil infiltration and leukotriene B₄ production by neutrophils. Here, we showed that mead acid also suppresses retinol-induced irritant contact dermatitis. In a murine model, we revealed that mead acid inhibited keratinocyte abnormalities such as keratinocyte hyperproliferation. Consistently, mead acid inhibited p38 MAPK (mitogen-activated protein kinase) phosphorylation, which is an essential signaling pathway in the keratinocyte hyperplasia induced by retinol. These inhibitory effects of mead acid were associated with the prevention of both keratinocyte hyperproliferation and the gene expression of neutrophil chemoattractants, including Cxcl1 and Cxcl2, and they were mediated by a PPAR (peroxisome proliferator-activated receptor)-α pathway. Our findings identified the anti-inflammatory effects of mead acid, the use of which can be expected to minimize the risk of adverse side effects associated with topical retinoid application.

Keywords: hyperproliferation; inflammation; irritant contact dermatitis (ICD); keratinocyte; lipid metabolite; mead acid; oleic acid; retinol.

Grants and funding

This work was supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT)/Japan Society for the Promotion of Science KAKENHI (grant numbers 21K20769 to AS; 19K07617 to TN; 22K15004 to KH; and 21H02757 to JK); the Japan Agency for Medical Research and Development (AMED; grant number 22ae0121035s012 to KH and grant numbers 22fk0108145h0003, 22ae0121042h0002, and 223fa727001h0001 to JK); the Ministry of Health and Welfare of Japan and Public/Private R&D Investment Strategic Expansion Program: PRISM (grant number 20AC5004 to JK); the Cross-Ministerial Strategic Innovation Promotion Program (SIP) (grant number 18087292 to JK); the Grant for the Joint Research Project of the Institute of Medical Science, the University of Tokyo (to JK); the Ono Medical Research Foundation (to JK); and the Canon Foundation (to JK).