Alox8 knockout exacerbates imiquimod-induced psoriasis-like inflammation

Area of Science:

• Biochemistry
• Immunology
• Dermatology

Background:

• Lipoxygenases produce oxylipins, influencing inflammation.
• Arachidonate 15-lipoxygenase type B is implicated in keratinocyte inflammation resolution.
• Murine arachidonate 8-lipoxygenase (Alox8) differs in oxygen addition site compared to human orthologs.

Purpose of the Study:

• To investigate the role of Alox8 in resolving imiquimod-induced psoriasis in mice.
• To characterize the effects of Alox8 deficiency on skin inflammation and lipid profiles.

Main Methods:

• Generation of Alox8 knockout (KO) mice by targeting the enzyme's active site.
• Untargeted lipidomics and LC-MS/MS analysis of skin samples.
• Assessment of epidermal changes, immune cell infiltration, and cytokine/mediator levels.

Main Results:

• Alox8 KO mice displayed exacerbated and prolonged psoriasis-like skin inflammation.
• Reduced levels of Alox8-specific oxylipins and 4-hydroxynonenal were observed in Alox8 KO mice.
• Alox8 deficiency led to increased epidermal thickness, immune cell infiltration (including γδ T cells), and elevated pro-inflammatory cytokines (IL-17, IL-22).

Conclusions:

• Alox8 plays a significant role in the resolution of murine psoriasis.
• Alox8 deficiency results in an exacerbated inflammatory phenotype, suggesting a protective role in skin inflammation.