Knockout of Cyp26a1 and Cyp26b1 during postnatal life causes reduced lifespan, dermatitis, splenomegaly, and systemic inflammation in mice

Abstract

All-trans-retinoic acid (atRA), the active metabolite of vitamin A, is an essential signaling molecule in all chordates. Global knockouts of the atRA clearing enzymes Cyp26a1 or Cyp26b1 are embryonic lethal. In adult rodents, inhibition of Cyp26a1 and Cyp26b1 increases atRA concentrations and signaling. However, postnatal knockout of Cyp26a1 does not cause a severe phenotype. We hypothesized that Cyp26b1 is the main atRA 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 atRA concentrations in the skin while the postnatal knockout of both Cyp26a1 and Cyp26b1 resulted in increased atRA concentrations in the liver, serum, skin, spleen, and intestines. This study demonstrates the paramount role of Cyp26b1 in regulating retinoid homeostasis in postnatal life. K E Y W O R D S cytochrome P450, dermatitis, inflammation, retinoic acid, vitamin A 2 | SNYDER Et al. 2 | MATERIALS AND METHODS 2.1 | Ethics statement, animal care, and breeding All the procedures involving mice prior to the commencement of these studies were approved by the Washington State University Committee on the Use and Care of Animals. The mouse colonies were maintained in a temperature-and humidity-controlled environment with food and water provided ad libitum. The mice were fed LabDiet 5K67 containing 1.5 ppm of carotene and 20 IU/g of vitamin

Immunomodulatory Microparticles Epigenetically Modulate T Cells and Systemically Ameliorate Autoimmune Arthritis

“…[53][54][55]79,80] The calculated maximum systemic exposure to ATRA in vivo after a single IA PLGA-ATRA MP injection (C max ) is 40 × 10 −12 m, well below the concentrations reached with doses that have been associated with toxicity in rodents (>14 mg kg −1 ). [81,82] These results are consistent with prior work that evaluated sustained release and systemic concentration of ATRA following a subcutaneous dose. [83] Moreover, our pharmacokinetic model shows that a therapeutically relevant concentration of ATRA is maintained in the synovial fluid of the treated joint and the immunization experiment demonstrates that IA released ATRA avoids generalized immune suppression.…”

Immunomodulatory Microparticles Epigenetically Modulate T Cells and Systemically Ameliorate Autoimmune Arthritis

“…[53][54][55]79,80] The calculated maximum systemic exposure to ATRA in vivo after a single IA PLGA-ATRA MP injection (C max ) is 40 × 10 −12 m, well below the concentrations reached with doses that have been associated with toxicity in rodents (>14 mg kg −1 ). [81,82] These results are consistent with prior work that evaluated sustained release and systemic concentration of ATRA following a subcutaneous dose. [83] Moreover, our pharmacokinetic model shows that a therapeutically relevant concentration of ATRA is maintained in the synovial fluid of the treated joint and the immunization experiment demonstrates that IA released ATRA avoids generalized immune suppression.…”

Serine Glycine Restriction Aggravates Hepatic Ischemia–reperfusion Injury

“… 33 CYP2S1 can inhibit inflammation, 34 whereas CYP26B1 knockout can induce systemic inflammation in mice. 35 In this study, both CYP2S1 and CYP26B1 were significantly downregulated, and their overexpression significantly protected against hypoxia-induced hepatocyte injury under −SG medium, inhibited hepatocyte apoptosis, reduced inflammation, and increased hepatocyte activity. Notably, amplification and overexpression of the CYP2A22 homologous gene CYP2A6 can increase cancer malignancy.…”

Differential responsiveness of spermatogonia to retinoic acid dictates precocious differentiation but not meiotic entry during steady-state spermatogenesis

“…This markedly differed from results in the developing testis, where RA catabolism conferred a near-complete degree of protection of undifferentiated progenitor spermatogonia from RA [16]. This aligns with results from mice with Sertoli cell-specific deletion of Cyp26b1 , which encodes the CYP26 enzyme active in the testis—those mice had severe disruptions in spermatogenesis in younger mice that improved as the mice aged [20, 66].…”

Immunomodulatory Microparticles Epigenetically Modulate T Cells and Systemically Ameliorate Autoimmune Arthritis

“…[53][54][55]79,80] The calculated maximum systemic exposure to ATRA in vivo after a single IA PLGA-ATRA MP injection (C max ) is 40 × 10 −12 m, well below the concentrations reached with doses that have been associated with toxicity in rodents (>14 mg kg −1 ). [81,82] These results are consistent with prior work that evaluated sustained release and systemic concentration of ATRA following a subcutaneous dose. [83] Moreover, our pharmacokinetic model shows that a therapeutically relevant concentration of ATRA is maintained in the synovial fluid of the treated joint and the immunization experiment demonstrates that IA released ATRA avoids generalized immune suppression.…”

Serine Glycine Restriction Aggravates Hepatic Ischemia–reperfusion Injury

“… 33 CYP2S1 can inhibit inflammation, 34 whereas CYP26B1 knockout can induce systemic inflammation in mice. 35 In this study, both CYP2S1 and CYP26B1 were significantly downregulated, and their overexpression significantly protected against hypoxia-induced hepatocyte injury under −SG medium, inhibited hepatocyte apoptosis, reduced inflammation, and increased hepatocyte activity. Notably, amplification and overexpression of the CYP2A22 homologous gene CYP2A6 can increase cancer malignancy.…”

Differential responsiveness of spermatogonia to retinoic acid dictates precocious differentiation but not meiotic entry during steady-state spermatogenesis

“…This markedly differed from results in the developing testis, where RA catabolism conferred a near-complete degree of protection of undifferentiated progenitor spermatogonia from RA [16]. This aligns with results from mice with Sertoli cell-specific deletion of Cyp26b1 , which encodes the CYP26 enzyme active in the testis—those mice had severe disruptions in spermatogenesis in younger mice that improved as the mice aged [20, 66].…”

Immunomodulatory Microparticles Epigenetically Modulate T Cells and Systemically Ameliorate Autoimmune Arthritis

“…[53][54][55]79,80] The calculated maximum systemic exposure to ATRA in vivo after a single IA PLGA-ATRA MP injection (C max ) is 40 × 10 −12 m, well below the concentrations reached with doses that have been associated with toxicity in rodents (>14 mg kg −1 ). [81,82] These results are consistent with prior work that evaluated sustained release and systemic concentration of ATRA following a subcutaneous dose. [83] Moreover, our pharmacokinetic model shows that a therapeutically relevant concentration of ATRA is maintained in the synovial fluid of the treated joint and the immunization experiment demonstrates that IA released ATRA avoids generalized immune suppression.…”

Serine Glycine Restriction Aggravates Hepatic Ischemia–reperfusion Injury

“… 33 CYP2S1 can inhibit inflammation, 34 whereas CYP26B1 knockout can induce systemic inflammation in mice. 35 In this study, both CYP2S1 and CYP26B1 were significantly downregulated, and their overexpression significantly protected against hypoxia-induced hepatocyte injury under −SG medium, inhibited hepatocyte apoptosis, reduced inflammation, and increased hepatocyte activity. Notably, amplification and overexpression of the CYP2A22 homologous gene CYP2A6 can increase cancer malignancy.…”

Differential responsiveness of spermatogonia to retinoic acid dictates precocious differentiation but not meiotic entry during steady-state spermatogenesis

“…This markedly differed from results in the developing testis, where RA catabolism conferred a near-complete degree of protection of undifferentiated progenitor spermatogonia from RA [16]. This aligns with results from mice with Sertoli cell-specific deletion of Cyp26b1 , which encodes the CYP26 enzyme active in the testis—those mice had severe disruptions in spermatogenesis in younger mice that improved as the mice aged [20, 66].…”