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

Abstract

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. PI3Kδ and PI3Kγ play important roles in various immune cell functions. We found that mice lacking functional PI3Kδ or PI3Kγ 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. TCRγδ T cells were the major IL-17–producing population in the draining lymph nodes and were significantly diminished in IMQ-treated PI3Kδ knockin and PI3Kγ knockout mice. We also show that PI3Kδ and PI3Kγ inhibitors reduced IFN-γ production by human TCRγδ T cells and IL-17 and IFN-γ production by PBMCs from psoriatic or healthy donors. In addition, inhibition of PI3Kγ, but not PI3Kδ, blocked chemotaxis of CCR6+IL-17–producing cells from IMQ-treated mice or healthy human donors. Taken together, these data indicate that PI3Kδ and/or PI3Kγ inhibitors should be considered for treating IL-17–driven diseases, such as psoriasis.

Interleukin 17 Drives Vascular Inflammation, Endothelial Dysfunction, and Arterial Hypertension in Psoriasis-Like Skin Disease

“…This is comparable to psoriasis patients, where a positive correlation between the psoriasis area and severity index score and the serum IL-17 level has been described. 26,27 Elevated IL-17A serum levels have also been reported for the imiquimod-induced psoriasis-like skin disease (≈20-40 pg/ mL in IMQ-treated wildtype mice, barely detectable in control mice), 36 although less in comparison to the K14IL-17A ind/+ mice, which can be explained by the smaller area of affected skin. The elevated IL-17A levels in the serum of the K14IL-17A ind/+ mice were accompanied by increased numbers of CD11b + cells-mostly neutrophil granulocytes-in the blood (Figure 2A-2C).…”

AMPK/HuR-Driven IL-20 Post-Transcriptional Regulation in Psoriatic Skin

“…Finally, the phosphatidylinositol 3-kinase/AKT/mammalian target of the rapamycin (PI3K/AKT/ mTOR) pathway is also targeted by HuR cytoplasmic relocalization, as indicated by the Kyoto Encyclopedia of Genes and Genomes occurrences of inositol phosphate metabolism, mTOR, phosphatidylinositol, and insulin signaling pathways. Positive feedback of HuR in the AKT pathway, which is involved in the pathogenesis of psoriasis, (Mitra et al, 2012;Roller et al, 2012;Buerger et al, 2013), has been reported (Singh et al, 2013). G Garcin et al…”

PI3K signaling in arterial diseases: Non redundant functions of the PI3K isoforms

“…Using chemical inhibitors has also given insight into the roles of different isoforms, for example a PI3Kd/g inhibitor (IPI-145) led to a decrease in IL-17 production in a model of inflammatory arthritis, suggesting an inhibitory effect on Th17 differentiation (Boyle et al, 2014). Moreover, the blockade of PI3Kd or g reduced IL-17 and ameliorated imiquimod-induced psoriasis-like dermatitis (Roller et al, 2012).…”