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

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. Pparg-/-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 Pparg-/-epi mouse skin included Igfl3, 2610528A11Rik, and Il1f6. 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 Igflr1, which encodes the receptor for Igfl3, and the 2610528A11Rik receptor (Gpr15). Transcripts for Il4 were detected in Pparg-/-epi mouse skin, but transcripts for Il17 and Il22 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 Pparg 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.

Fifty years of the asebia mouse: origins, insights and contemporary developments.

First described as an alopecic spontaneous mutant mouse line lacking sebaceous glands in a publication in Science in 1965 by Allen H. Gates and Marvin Karasek, asebia mice soon became a popular tool for rodent sebaceous gland research. In addition to the study of sebaceous lipids, the original asebia mice and subsequent allelic mutations were widely employed to examine the influence of the sebaceous gland on hair growth, epidermal proliferation, dermal inflammation and skin carcinogenesis, among other aspects. With the identification of Scd1 gene mutations as the genetic basis of the asebia phenotype and with the advent of more refined methods for manipulating the mouse genome, asebia mice progressively lost importance. However, they contributed to, or even provided the initial spark for, several current research topics. These include the role of the sebaceous gland in hair shaft-sheath interaction and its significance for cicatricial alopecia, and the antimicrobial activity of sebum. Furthermore, mice with skin-specific deletion of SCD1, which have increased energy expenditure and are protected from high fat diet-induced obesity, provided novel insights into the crosstalk between the skin and peripheral tissues in maintaining energy homeostasis. In briefly reviewing its story, this commentary pays tribute to asebia mice and to the original publication in its golden anniversary year.