**Background:** Psoriasis is a chronic inflammatory skin disorder with unclear pathogenesis, though T-cell mediated processes, particularly the IL-23/Th17 axis, are implicated. Obesity is clinically associated with more severe psoriasis and poorer treatment responses, but the underlying mechanisms remain poorly understood. This study aimed to investigate the role of obesity in exacerbating psoriasis using an imiquimod-induced murine model, focusing on IL-6 and Th17 immune responses.
**Methods:** Female C57BL/6 mice (8–10 weeks old) were divided into two groups and fed either a regular diet (RD) or an obesity-inducing high-fat diet (OID, 40% fat) for 20 weeks. OID was defined as mean body weight >3 SD above the RD group mean. Psoriasis was induced by daily topical application of 80 mg of 5% imiquimod cream on shaved backs for 7 consecutive days. Control groups received Vaseline. Experimental groups included: RD control (n=36, 24.63±1.27 g), RD disease (n=40, 24.56±1.09 g), OID control (n=36, 39.15±4.27 g), and OID disease (n=40, 42.07±6.38 g). Skin inflammation was scored daily for erythema, scaling, and thickness (0–4 scale each, cumulative 0–12). Histopathology was performed on days 1, 2, 4, and 7 with H&E staining. Serum IL-6 and TNF-α were measured by CBA at baseline and days 1, 2, 4, and 7. Th17 cell populations (CD3+CD4+IL-17+) in spleen and draining lymph nodes were analyzed by flow cytometry on day 7. Additionally, cells from spleen and lymph nodes were stimulated with anti-CD3/anti-CD28 for 72 hours, and IL-17, IL-6, and TNF-α in supernatants were measured.
**Key Results:** Clinical symptom scores were significantly higher in the OID group compared to the RD group throughout the 7-day treatment period. Epidermal thickness after 7 days was significantly greater in OID mice (69.2±4.26 μm) than in RD mice (58.11±1.52 μm, p<0.001). Intra-corneal microabscesses (Munro's microabscesses), a characteristic feature of psoriasis, appeared earlier in OID mice (day 2) than in RD mice (day 4). Serum IL-6 and TNF-α levels increased after imiquimod treatment in both groups, but differences between OID and RD were not statistically significant at any time point. Th17 cell percentages in spleen were highest in imiquimod-treated OID (8.82±0.51%), followed by imiquimod-treated RD (6.74±0.45%), non-treated OID (6.15±0.63%), and non-treated RD (4.10±0.38%). Differences between imiquimod-treated OID vs. RD and non-treated OID vs. RD were statistically significant (p<0.05 to p<0.001). Similar trends were observed in draining lymph nodes: imiquimod-treated OID (5.64±0.51%), imiquimod-treated RD (4.15±0.09%), non-treated OID (3.94±0.11%), and non-treated RD (3.19±0.19%). IL-17 secretion from stimulated spleen and lymph node cells was significantly higher in the OID group than the RD group (p<0.05). IL-6 and TNF-α secretion from stimulated cells were higher in OID but not statistically significant.
**Clinical Implications:** This study provides mechanistic evidence that obesity exacerbates psoriasis through enhanced Th17 cell differentiation and IL-17 production, likely driven by increased IL-6 from adipose tissue. The findings suggest that obese psoriatic patients may benefit from therapies targeting the IL-6/Th17/IL-17 axis, and that weight management could be an important adjunctive strategy. The imiquimod-induced psoriasis model in obese mice may serve as a valuable tool for testing novel treatments for this patient population. Limitations include the inability to fully explain the transition from non-pathogenic to pathogenic Th17 cells and the lack of IL-23 evaluation.