Besides genetic alterations, the cellular environment also determines disease onset and progression. When different cell types contribute to disease outcome, this imposes environmental challenges as different cell types likely differ in their extracellular dependencies. Hsa‐microRNA‐31‐5p (miR‐31) is highly expressed in keratinocytes of psoriatic skin, and we show that expression in keratinocytes is induced by limited glucose availability and enables increased survival under limiting glucose conditions by increasing glutamine metabolism. In addition, miR‐31 expression results in not only secretion of specific metabolites (aspartate and glutamate) but also secretion of immunomodulatory factors. We show that this miR‐31‐induced secretory phenotype is sufficient to induce Th17 cell differentiation, a hallmark of psoriasis. Inhibitors of miR31‐induced metabolic rewiring and metabolic crosstalk with immune cells alleviate psoriasis pathology in a mouse model of psoriasis. Together our data illustrate an emerging concept of metabolic interaction across cell compartments that characterizes disease development, which can be employed to design effective treatment options for disease, as shown here for psoriasis. Synopsis MiR‐31 expression, a marker of psoriasis, redirects keratinocyte metabolism to support survival of cells in the spinous layer and to induce Th17 cell differentiation. Pharmacological inhibition of miR‐31‐induced metabolic changes relieves psoriatic disease in an animal model. MiR‐31 expression in the spinous layer of psoriatic skin induces a redirection of metabolism toward glutamine utilization MiR‐31‐induced metabolic changes in keratinocytes contribute to the induction of Th17 differentiation Targeting miR‐31‐induced metabolic changes alleviates psoriasis pathology MiR‐31 expression, a marker of psoriasis, redirects keratinocyte metabolism to support survival of cells in the spinous layer and to induce Th17 cell differentiation. Pharmacological inhibition of miR‐31‐induced metabolic changes relieves psoriatic disease in an animal model.