RESUMEN
Psoriasis is a chronic inflammatory skin disease marked by aberrant tissue repair. Mutant mice modeling psoriasis skin characteristics have provided useful information relevant to molecular mechanisms and could serve to evaluate therapeutic strategies. Here, we found that epidermal ANGPTL6 expression was markedly induced during tissue repair in mice. Analysis of mice overexpressing ANGPTL6 in keratinocytes (K14-Angptl6 Tg mice) revealed that epidermal ANGPTL6 activity promotes aberrant epidermal barrier function due to hyperproliferation of prematurely differentiated keratinocytes. Moreover, skin tissues of K14-Angptl6 Tg mice showed aberrantly activated skin tissue inflammation seen in psoriasis. Levels of the proteins S100A9, recently proposed as therapeutic targets for psoriasis, also increased in skin tissue of K14-Angptl6 Tg mice, but psoriasis-like inflammatory phenotypes in those mice were not rescued by S100A9 deletion. This finding suggests that decreasing S100A9 levels may not ameliorate all cases of psoriasis and that diverse mechanisms underlie the condition. Finally, we observed enhanced levels of epidermal ANGPTL6 in tissue specimens from some psoriasis patients. We conclude that the K14-Angptl6 Tg mouse is useful to investigate psoriasis pathogenesis and for preclinical testing of new therapeutics. Our study also suggests that ANGPTL6 activation in keratinocytes enhances psoriasis susceptibility.
Asunto(s)
Proteínas Similares a la Angiopoyetina/genética , Calgranulina A/genética , Calgranulina B/genética , Queratinocitos/metabolismo , Psoriasis/genética , Adulto , Proteína 6 similar a la Angiopoyetina , Proteínas Similares a la Angiopoyetina/metabolismo , Animales , Calgranulina A/metabolismo , Calgranulina B/metabolismo , Estudios de Casos y Controles , Modelos Animales de Enfermedad , Epidermis/metabolismo , Epidermis/patología , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Humanos , Queratinocitos/patología , Masculino , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Psoriasis/metabolismo , Psoriasis/patología , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
The biosynthetic origin of the C(3) branched unit of agglomerin A has been investigated. Feeding of sn-(3R)- and sn-(3S)-[3-(2)H]glycerols to Enterobacter agglomerans PB-6042 followed by (2)H NMR analysis of the resulting agglomerin A revealed that pro-R and pro-S hydrogens at sn-C-3 of glycerol were incorporated stereospecifically into 5E and 5Z hydrogens of agglomerin A, respectively. These results imply that the immediate precursor of the C(3) branched unit is not pyruvate, but 1,3-bisphosphoglyceric acid or its biological equivalent.