590 Increased psoriasis severity with obesity is associated with insufficient adiponectin-mediated regulatory T cell response

Abstract

Psoriasis is a chronic inflammatory skin disease characterized by Th17 cell skewing. Obesity, the most common psoriasis co-morbidity, is associated with greater disease severity. We showed earlier onset and greater disease severity, as well as reduced adiponectin expression, in high fat diet (HFD)-fed obese mice compared to regular diet (RD)-fed controls when psoriasis-like disease is induced by topically-applied imiquimod (IMQ). Obesity is associated with a reduced Treg response, but its role in psoriasis is unknown. We postulated that insufficient lesional Treg cells may promote greater severity of psoriasis with obesity. Immunohistochemical analysis of lesional skin of RD mice treated with IMQ to induce psoriasis revealed increased resident Treg cells compared with healthy (NT) skin (IMQ 116.7cells/mm2 vs. NT 51.1 cells/mm2, p<0.01). In obese mice, IMQ fails to increase Treg cells (16.5 cells/mm2, p<0.001 vs. IMQ-treated RD mice; p=0.99 vs. HFD mice without IMQ) and increases psoriasis severity. Intraperitoneal treatment with ADP355, an adiponectin mimetic, restores in HFD mice IMQ-induced Treg upregulation (80.15 cells/mm2; p=0.67 vs RD mice) and improves psoriasis-like disease severity (reducing modified Psoriasis Areas and Severity Index/PASI by 40.9%, p<0.01; epidermal thickness by 39%, p<0.01; and epidermal hyper-proliferation by 56%, <0.001), and expression of psoriasis-associated inflammatory markers (TNFA by 98%, DEFB4 97%, PI3 89%, IL17A 73%, IL6 57%, and IL22 49%; all p<0.001 vs. vehicle-injected HFD mice). PBMCs exposed to 72 h of TGF-β plus IL-2 yielded no increase in CD25+/FOXP3+ cells with ADP355 vs. PBS, suggesting that adiponectin mediates Treg cell recruitment or survival, but not differentiation. Overall, our findings suggest that adiponectin deficiency may contribute to the greater severity of psoriasis in obesity through a reduced regional Treg cell response.