Background <p>MicroRNAs (miRNAs) are short regulatory RNAs that can be released in extracellular vesicles and, under pathological conditions such as autoimmunity, activate innate immune cells through Toll-like receptor (TLR) 7 and 8. This mechanism may sustain chronic inflammation. Psoriasis is an immune-mediated skin disease where the role and activation pathways of Natural Killer (NK) cells remain incompletely understood. We investigated whether miRNAs upregulated in psoriatic lesions contribute to NK cell activation.</p> Methods <p>A pool of psoriasis-associated miRNAs (pso-miR) was generated and used to stimulate either purified NK cells or peripheral blood mononuclear cells (PBMCs). NK cell activation was assessed in terms of cytokine secretion and target cell killing. Inhibitor experiments were performed to demonstrate TLR activation by pso-miR.</p> Results <p>Pso-miR did not directly activate NK cells, which lack TLR7/8, but triggered NK effector functions, including IFN-γ secretion and cytotoxicity, within PBMCs, indicating the involvement of accessory cells. Mechanistically, pso-miR engaged TLR7/8-expressing plasmacytoid dendritic cells and monocytes, leading to the secretion of IFN-α, IL-12, and IL-18. These cytokines, in turn, drove full NK cell activation. We also identified a previously overlooked subset of CD56^dim NK cells in psoriatic skin, representing mature cytotoxic NKs. Moreover, pso-miR stimulation of PBMCs induced IFN-γ-producing CD8⁺ T cells, further amplifying tissue-damaging responses.</p> Conclusions <p>Altogether, these findings reveal that psoriatic miRNAs activate an innate immune loop, which indirectly drives NK cell and CD8⁺ T cell effector functions via TLR7/8-dependent cytokine signalling, representing a novel pathogenic mechanism of psoriatic inflammation and keratinocyte damage. Of note, such miRNA-mediated crosstalk is abrogated by the dual TLR7/8 antagonist Enpatoran, highlighting a therapeutic avenue for modulating immune activation in psoriasis.</p>