Exaggerated IL-23-induced psoriasis-like inflammation in mice lacking CCR4 (135.32)

Abstract

Abstract Recent evidence strongly implicates the IL-23/Th17/Th22 axis in psoriasis, and intradermal injection of IL-23 produces local psoriasis-like inflammation, which depends on IL-22 and other IL-10-family cytokines. CCR4 is a chemokine receptor thought to be important for T cell trafficking to skin, and is expressed on all Th2 cells, as well as many Th17 cells and Treg. We tested CCR4 deficient mice in the IL-23 injection model and found, surprisingly, that they had an exaggerated inflammatory response, with increased swelling of the injected skin, greater acanthosis, parakeratosis, and microabscess formation, higher numbers of infiltrating neutrophils, T cells and dendritic cells, and higher numbers of pro-inflammatory cytokines, including: IL-17a, IL-17f, IL-19, IL-22 and TNFα. Remarkably, despite the greater inflammation, Foxp3+ cells were not increased in the IL-23-injected skin of the CCR4 deficient mice, producing a higher effector T cell/Treg ratio as compared with wild-type mice. Our results suggest that CCR4 is important, not for effector functions, but for recruiting cells to down-modulate Th17/Th22-mediated inflammation in skin. These findings may help in understanding how inflammation is regulated in psoriasis and related disorders. Supported by the Intramural Research Program, NIH, NIAID.