Cell type-specific targeting dissociates the therapeutic from the adverse effects of protein kinase inhibition in allergic skin disease

Abstract

The kinase p38 alpha, originally identified because of its endotoxin- and cytokine-inducible activity and affinity for antiinflammatory compounds, has been posited as a promising therapeutic target for various immune-mediated disorders. In clinical trials, however, p38 alpha inhibitors produced adverse skin reactions and other toxic effects that often outweighed their benefits. Such toxicity may arise from a perturbation of physiological functions unrelated to or even protective against the disease being treated. Here, we show that the effect of interfering with p38 alpha signaling can be therapeutic or adverse depending on the targeted cell type. Using a panel of mutant mice devoid of p38 alpha in distinct cell types and an experimental model of allergic skin disease, we find that dendritic cell (DC)-intrinsic p38 alpha function is crucial for both antigen-specific T-cell priming and T-cell-mediated skin inflammation, two independent processes essential for the immunopathogenesis. By contrast, p38 alpha in other cell types serves to prevent excessive inflammation or maintain naive T-cell pools in the peripheral lymphoid tissues. These findings highlight a dilemma in the clinical use of p38 alpha inhibitors, yet also suggest cell-selective targeting as a potential solution for improving their therapeutic index.