Alox8 knockout exacerbates imiquimod-induced psoriasis-like inflammation

Abstract Lipoxygenases peroxidise polyunsaturated fatty acids, resulting in oxylipins, which may act pro- or anti-inflammatory. Arachidonate 15-lipoxygenase type B was shown to play a role in the resolution of keratinocyte inflammation and is upregulated in psoriasis. Its murine ortholog, arachidonate 8-lipoxygenase (Alox8), differs in regiospecificity in that it adds molecular oxygen to the 8th and not 15th carbon of arachidonic acid. This study aimed to determine if Alox8 plays a role in the resolution of murine imiquimod-induced psoriasis. Alox8 knockout (KO) mice, which are not commercially available, were generated with a functional KO targeting the enzyme’s active site. Untargeted Lipidomics revealed changes in the skin lipidome from both imiquimod-induced psoriasis as well as between wild-type and KO mice. Furthermore, LC-MS/MS revealed a functional KO with reductions in Alox8-specific oxylipins. Lipid peroxidation marker 4-hydroxynonenal was elevated in the epidermis of wild-type mice from imiquimod treatment, however, it was significantly reduced in Alox8 KO mice. Alox8 KO mice exhibited a thickened epidermis, resulting from reduced DNA damage and increased proliferation. Moreover, immune cell infiltration was enhanced in Alox8 KO mice, including a higher abundance of γδ T cells. Elevated cytokine levels of interleukin-17 and -22, accompanied by keratinocyte-produced C-X-C motif chemokine ligand 1, were detected in the skin of Alox8 KO mice. Additionally, cyclooxygenase 2 expression and prostaglandin E 2 levels were enhanced in Alox8 KO mice. These data demonstrate an exacerbated and prolonged inflammatory psoriasis phenotype in Alox8 KO mice, implying that Alox8 aids in the resolution of murine psoriasis.