Greater psoriatic disease progression in male BALB/c mice: implications for preclinical modeling

Psoriasis is a chronic inflammatory skin disorder driven by immune dysregulation and characterized by epidermal thickening, redness, and scaling. Although autoimmune conditions are more common in females, limited preclinical evidence addresses sex as a determinant of psoriasis pathogenesis. Here, we examined sex-dependent differences in psoriasis-like inflammation in BALB/c mice treated topically with 5% imiquimod (IMQ) for seven days. Disease severity was evaluated by Psoriasis Area and Severity Index (PASI), histopathology, spleno-somatic index (SSI), and molecular analyses. Male mice developed more severe disease, with higher PASI scores, pronounced epidermal hyperplasia, and denser immune infiltration than females. SSI elevation in males further indicated enhanced systemic immune activation. qPCR analysis revealed stronger upregulation of pro-inflammatory and proliferative genes (Tlr7, Il-17a, Il-6, Tnf-α, Ifn-γ, Il-23a, Jak1, Stat3, and Nf-κb) in males compared with females. Notably, regulatory cytokine analysis showed reduced IL-10 but increased TGF-β mRNA expression in males, indicating an imbalance between anti-inflammatory and regulatory pathways. Consistent with transcriptional findings, Western blot analysis demonstrated elevated protein expression of TLR7 and NF-κB p65, confirming enhanced inflammatory signaling, while TGF-β protein was upregulated in males, further supporting sex-dependent immune modulation. These findings indicate that male BALB/c mice display heightened susceptibility to IMQ-induced psoriatic inflammation both locally and systemically. The observed sex-based differences underscore the importance of incorporating sex as a biological variable in psoriasis research, thereby improving the translational accuracy of preclinical models and supporting the development of more individualized therapeutic strategies.