A Sex-Specific Anti-Inflammatory Role for p62 in Psoriasis-Like Disease

Psoriasis is a chronic inflammatory skin disease involving a complex cross-talk between immune and epidermal cells. Psoriasis is difficult to treat and often complicated by systemic manifestations such as psoriatic arthritis. SQSTM1/p62 is a multifunctional adaptor protein controlling autophagy, cell differentiation, and inflammation that was found elevated in human psoriatic skin. We functionally evaluated the role of p62 in the cutaneous and systemic psoriasis-like phenotypes of a mouse model with inducible epidermal inactivation of c-Jun and JunB (ie, DKO∗). A male-specific aggravation of skin and joint disease was observed in DKO∗ mice when crossed with p62^-/- mice (DKO∗ p62^-/-). Thickened epidermis, disturbed keratinocyte differentiation, enhanced immune cell infiltration, and increased CXCL1 expression were exclusively observed in the skin of male DKO∗ p62^-/- mice. Increased androgen receptor protein expression and activation of androgen receptor signaling as well as upregulated inflammasome and KEAP1/NRF2 activities were apparent in the skin of male DKO∗ p62^-/- mice and were likely responsible for disease worsening. Our results describe a sex-specific anti-inflammatory role for p62 in psoriasis-like disease that could be relevant in the clinical setting.