Knockout of Cyp26a1 and Cyp26b1 during postnatal life causes reduced lifespan, dermatitis, splenomegaly, and systemic inflammation in mice. Issue 12 (26th October 2020)

• Record Type: Journal Article
• Authors: Snyder, Jessica M.; Zhong, Guo; Hogarth, Cathryn; Huang, Weize; Topping, Traci; LaFrance, Jeffrey; Palau, Laura; Czuba, Lindsay C.; Griswold, Michael; Ghiaur, Gabriel; Isoherranen, Nina
• Is Part Of: FASEB journal. Volume 34:Issue 12(2020)
• Page Start: 15788
• Page End: 15804
• Publication Date: 2020-10-26
• Subjects: cytochrome P450 -- dermatitis -- inflammation -- retinoic acid -- vitamin A; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.202001734R
• Languages: English
• ISSNs: 0892-6638

Abstract

Abstract: All‐ trans ‐retinoic acid ( at RA), the active metabolite of vitamin A, is an essential signaling molecule in all chordates. Global knockouts of the at RA clearing enzymes Cyp26a1 or Cyp26b1 are embryonic lethal. In adult rodents, inhibition of Cyp26a1 and Cyp26b1 increases at RA concentrations and signaling. However, postnatal knockout of Cyp26a1 does not cause a severe phenotype. We hypothesized that Cyp26b1 is the main at RA clearing Cyp in postnatal mammals. This hypothesis was tested by generating tamoxifen‐inducible knockout mouse models of Cyp26b1 alone or with Cyp26a1. Both mouse models showed dermatitis, blepharitis, and splenomegaly. Histology showed infiltration of inflammatory cells including neutrophils and T lymphocytes into the skin and hyperkeratosis/hyperplasia of the nonglandular stomach. The mice lacking both Cyp26a1 and Cyp26b1 also had a reduced lifespan, failed to gain weight, and showed fat atrophy. There were significant changes in vitamin A homeostasis. Postnatal knockout of Cyp26b1 resulted in increased at RA concentrations in the skin while the postnatal knockout of both Cyp26a1 and Cyp26b1 resulted in increased at RA concentrations in the liver, serum, skin, spleen, and intestines. This study demonstrates the paramount role of Cyp26b1 in regulating retinoid homeostasis in postnatal life.