Blockade of Phosphatidylinositol 3-Kinase (PI3K)δ or PI3Kγ Reduces IL-17 and Ameliorates Imiquimod-Induced Psoriasis-like Dermatitis

Psoriasis is a chronic inflammatory skin disease triggered by interplay between immune mediators from both innate and adaptive immune systems and skin tissue, in which the IL-23/IL-17 axis is critical. PI3K delta and PI3K gamma play important roles in various immune cell functions. We found that mice lacking functional PI3K delta or PI3K gamma are largely protected from imiquimod ( IMQ)-induced psoriasis-like dermatitis, correlating with reduced IL-17 levels in the lesions, serum, and the draining lymph nodes. TCR gamma delta T cells were the major IL-17-producing population in the draining lymph nodes and were significantly diminished in IMQ-treated PI3K delta knockin and PI3K gamma knockout mice. We also show that PI3K delta and PI3K gamma inhibitors reduced IFN-gamma production by human TCR gamma delta T cells and IL-17 and IFN-gamma production by PBMCs from psoriatic or healthy donors. In addition, inhibition of PI3K gamma, but not PI3K delta, blocked chemotaxis of CCR6(+)IL-17-producing cells from IMQ-treated mice or healthy human donors. Taken together, these data indicate that PI3K delta and/or PI3K gamma inhibitors should be considered for treating IL-17-driven diseases, such as psoriasis. The Journal of Immunology, 2012, 189: 4612-4620.