Retinoic acid (RA) is essential for maintenance of most epithelial tissues. One RA biosynthesis pathway consists of cellular retinol-binding protein (Crbp), retinol dehydrogenase (Dhrs9/eRoldh), retinal dehydrogenase 1-3 (Aldh1a1-3), and cellular RA-binding protein 2 (Crabp2). Previously, we localized Aldh1a2 and Aldh1a3 to both epithelial and mesenchymal cells within the hair follicle throughout the hair cycle. This study expands that observation by examining the complete pathway of RA biosynthesis and signaling via RA receptors alpha, beta, and gamma by immunohistochemistry in C57BL/6J mice wax-stripped to initiate and synchronize the cycle. This pathway of RA biosynthesis and signaling localized to the majority of layers of the hair follicle, sebaceous gland, and interfollicular epidermis in a hair cycle-dependent manner, suggesting that RA biosynthesis within the hair follicle is regulated in both a spatial and temporal manner. This localization pattern also revealed insights into epithelial-mesenchymal interactions and differentiation state differences within the RA biosynthesis and signaling pathway, as well as novel observations on nuclear versus cytoplasmic localization of Crabp2 and RA receptors. This complex pattern of RA biosynthesis and signaling identified by immunolocalization suggests that endogenous RA regulates specific aspects of hair follicle growth, differentiation, and cycling.

Alopecia areata (AA) is an autoimmune disease that attacks anagen hair follicles. Gene array in graft-induced C3H/HeJ mice revealed that genes involved in retinoic acid (RA) synthesis were increased, while RA degradation genes were decreased in AA compared to sham controls. This was confirmed by immunohistochemistry in biopsies from patients with AA and both mouse and rat AA models. RA levels were also increased in C3H/HeJ mice with AA. C3H/HeJ mice were fed a purified diet containing one of four levels of dietary vitamin A or an unpurified diet two weeks before grafting and disease progression followed. High vitamin A accelerated AA, while mice fed no vitamin A had more severe disease by the end of the study. More hair follicles were in anagen in mice fed high vitamin A. Both the number and localization of granzyme B positive cells were altered by vitamin A. IFNG was also lowest and IL13 highest in mice fed high vitamin A. Other cytokines were reduced and chemokines increased as the disease progressed, but no additional effects of vitamin A were seen. Combined, these results suggest that vitamin A regulates both the hair cycle and immune response to alter the progression of AA.

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Vitamin A and its derivatives (retinoids) are critically important in the development and maintenance of multiple epithelial tissues, including skin, hair, and sebaceous glands, as shown by the detrimental effects of either vitamin A deficiency or toxicity. Thus, precise levels of retinoic acid (RA, active metabolite) are needed. These precise levels of RA are achieved by regulating several steps in the conversion of dietary vitamin A (retinol) to RA and RA catabolism. This review discusses the localization of RA synthesis to specific sites within the hair follicle and sebaceous gland, including their stem cells, during both homeostasis and disease states. It also discusses what is known about the specific roles of RA within the hair follicle and sebaceous gland.

A number of C57BL/6 (B6) substrains are commonly used by scientists for basic biomedical research. One of several B6 strain specific background diseases is focal alopecia that may resolve or progress to severe, ulcerative dermatitis. Clinical and progressive histologic changes of skin disease commonly observed in C57BL/6J and preliminary studies in other closely related substrains are presented. Lesions develop due to a primary follicular dystrophy with rupture of severely affected follicles leading to formation of secondary foreign body granulomas (trichogranulomas) in affected B6 substrains of mice. Histologically these changes resemble the human disease called central centrifugal cicatrical alopecia (CCCA). Four B6 substrains tested have a polymorphism in alcohol dehydrogenase 4 (Adh4) that reduces its activity and potentially affects removal of excess retinol. Using immunohistochemistry, differential expression of epithelial retinol dehydrogenase (DHRS9) was detected which may partially explain anecdotal reports of frequency differences between B6 substrains. The combination of these two defects have the potential to make high dietary vitamin A levels toxic in some B6 substrains while not affecting most other commonly used inbred strains.