AbstractThe infiltration of neutrophils in the epidermis and the release of neutrophil extracellular traps (NETs) are important events in the pathogenesis of psoriasis, but the regulatory roles and internal mechanism of NETs in psoriasis are largely unknown. Here, we demonstrate that NETs can activate the absent‐in‐melanoma‐2 (AIM2) inflammasome in keratinocytes through the p38‐MAPK signalling pathway, and targeting NETs with CI‐amidine in vivo reduces AIM2 expression and ameliorates imiquimod‐induced psoriasis‐like phenotype in mice. Notably, NETs‐activated AIM2 in keratinocytes not only promotes IL‐1β production through the classical inflammasome pathway but also promotes IFN‐γ production via X‐linked inhibitor of apoptosis protein (XIAP), thereby mediating the immune responses of keratinocytes. In conclusion, our study demonstrates that the NETs‐AIM2 axis exerts multiple pro‐inflammatory effects on keratinocytes and may serve as a potential target for psoriasis therapy.