Lost and found in translation: the value of the human imiquimod model

Topical imiquimod (IMQ), a Toll-like receptor (TLR) 7 agonist, induces transient cutaneous inflammation and is widely used in preclinical research as a 'psoriasis-like' mouse model. However, accumulating evidence indicates substantial divergence between IMQ-driven biology and human plaque psoriasis pathogenesis. To bridge this translational gap, we compare here the experimental conduct, readouts and mechanistic insights engaged by IMQ challenge in mice vs. healthy human participants. Importantly, molecular and cellular analyses indicate that IMQ predominantly activates interferon regulatory factor (IRF) signalling in humans, rather than NF-κB pathways as observed in animals. Moreover, differences in neutrophil response and complement activation were also identified. These discrepancies may reflect interspecies variation in TLR7 expression as well as methodological differences between the animal and human IMQ model. Despite certain limitations related to psoriasis translatability, the human IMQ model has demonstrated translational relevance in several early phase clinical trials. It represents a valuable tool for evaluating target engagement and characterizing downstream pharmacodynamic effects of novel compounds, particularly those targeting the TLR7-IRF-type I interferon axis. In conclusion, the human IMQ model can serve as valuable mechanistic model driving disease-related pathways, rather than as a proxy for plaque psoriasis disease biology. Fit-for-purpose benchmarking and method standardization are essential to maximize translational utility of the IMQ model.