Poly(ADP) ribose polymerase-1 ablation alters eicosanoid and docosanoid signaling and metabolism in a murine model of contact hypersensitivity.

ABSTRACT

Poly(ADP­ribose) polymerase (PARP)­1 is a pro­inflammatory protein. The inhibition of PARP­1 reduces the activity of numerous pro­inflammatory transcription factors, which results in the reduced production of pro­inflammatory cytokines, chemokines, matrix metalloproteinases and inducible nitric oxide synthase, culminating in reduced inflammation of the skin and other organs. The aim of the present study was to investigate the effects of the deletion of PARP­1 expression on polyunsaturated fatty acids (PUFA), and PUFA metabolite composition, in mice under control conditions or undergoing an oxazolone (OXA)­induced contact hypersensitivity reaction (CHS). CHS was elicited using OXA in both the PARP­1+/+ and PARP­1/ mice, and the concentration of PUFAs and PUFA metabolites in the diseased skin were assessed using lipidomics experiments. The levels of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were shown to be increased in the PARP­1/ mice, as compared with the control, unsensitized PARP­1+/+ mice. In addition, higher expression levels of fatty acid binding protein 7 (FABP7) were detected in the PARP­1/ mice. FABP7 is considered to be a specific carrier of DHA and EPA. Furthermore, the levels of the metabolites of DHA and EPA (considered mainly as anti­inflammatory or pro­resolving factors) were higher, as compared with the metabolites of arachidonic acid (considered mainly pro­inflammatory), both in the unsensitized control and OXA­sensitized PARP­1/ mice. The results of the present study suggest that the genetic deletion of PARP­1 may affect the PUFA­homeostasis of the skin, resulting in an anti­inflammatory milieu, including increased DHA and EPA levels, and DHA and EPA metabolite levels. This may be an important component of the anti­inflammatory action of PARP­1 inhibition.