Epidermal PPARγ Is a Key Homeostatic Regulator of Cutaneous Inflammation and Barrier Function in Mouse Skin

• Main Authors: Raymond L. Konger, Ethel Derr-Yellin, Teresa A. Zimmers, Terrence Katona, Xiaoling Xuei, Yunlong Liu, Hong-Ming Zhou, Ed Ronald Simpson, Matthew J. Turner
• Format: Article
• Language: English
• Published: MDPI AG 2021-08-01
• Series: International Journal of Molecular Sciences
• Subjects: peroxisome proliferator-activated receptor gamma; transcriptomic changes; cutaneous phenotype; asebia
• Online Access: https://www.mdpi.com/1422-0067/22/16/8634
• ISSN: 1661-6596; 1422-0067

Both agonist studies and loss-of-function models indicate that PPARγ plays an important role in cutaneous biology. Since PPARγ has a high level of basal activity, we hypothesized that epidermal PPARγ would regulate normal homeostatic processes within the epidermis. In this current study, we performed mRNA sequencing and differential expression analysis of epidermal scrapings from knockout mice and wildtype littermates. <i>Pparg</i>-/-^epi mice exhibited a 1.5-fold or greater change in the expression of 11.8% of 14,482 identified transcripts. Up-regulated transcripts included those for a large number of cytokines/chemokines and their receptors, as well as genes associated with inflammasome activation and keratinization. Several of the most dramatically up-regulated pro-inflammatory genes in <i>Pparg</i>-/-^epi mouse skin included <i>Igfl3</i>, <i>2610528A11Rik</i>, and <i>Il1f6</i>. RT-PCR was performed from RNA obtained from non-lesional full-thickness skin and verified a marked increase in these transcripts, as well as transcripts for <i>Igflr1</i>, which encodes the receptor for Igfl3, and the 2610528A11Rik receptor (<i>Gpr15</i>). Transcripts for <i>Il4</i> were detected in <i>Pparg</i>-/-^epi mouse skin, but transcripts for <i>Il17</i> and <i>Il22</i> were not detected. Down-regulated transcripts included sebaceous gland markers and a number of genes associated with lipid barrier formation. The change in these transcripts correlates with an asebia phenotype, increased transepidermal water loss, alopecia, dandruff, and the appearance of spontaneous inflammatory skin lesions. Histologically, non-lesional skin showed hyperkeratosis, while inflammatory lesions were characterized by dermal inflammation and epidermal acanthosis, spongiosis, and parakeratosis. In conclusion, loss of epidermal <i>Pparg</i> alters a substantial set of genes that are associated with cutaneous inflammation, keratinization, and sebaceous gland function. The data indicate that epidermal PPARγ plays an important role in homeostatic epidermal function, particularly epidermal differentiation, barrier function, sebaceous gland development and function, and inflammatory signaling.