Mast Cells and Neutrophils Release IL-17 through Extracellular Trap Formation in Psoriasis

TLDR

IL‑17 and IL‑23 are central to psoriasis, and therapies that block these cytokines are highly effective by targeting IL‑17‑producing T cells and their IL‑23‑driven expansion. We show that mast cells and neutrophils, not T cells, are the main IL‑17–producing cells in psoriasis lesions, releasing IL‑17 through extracellular traps and that IL‑23 and IL‑1β stimulate mast cell trap formation and degranulation, suggesting innate immune IL‑17 release is key to disease pathogenesis.

Abstract

Abstract IL-17 and IL-23 are known to be absolutely central to psoriasis pathogenesis because drugs targeting either cytokine are highly effective treatments for this disease. The efficacy of these drugs has been attributed to blocking the function of IL-17–producing T cells and their IL-23–induced expansion. However, we demonstrate that mast cells and neutrophils, not T cells, are the predominant cell types that contain IL-17 in human skin. IL-17+ mast cells and neutrophils are found at higher densities than IL-17+ T cells in psoriasis lesions and frequently release IL-17 in the process of forming specialized structures called extracellular traps. Furthermore, we find that IL-23 and IL-1β can induce mast cell extracellular trap formation and degranulation of human mast cells. Release of IL-17 from innate immune cells may be central to the pathogenesis of psoriasis, representing a fundamental mechanism by which the IL-23–IL-17 axis mediates host defense and autoimmunity.