title: Blockade of phosphatidylinositol 3-kinase PI3Kδ 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.
authors.affiliation: Rheumatology Research, Merck Serono S.A., 1211 Geneva, Switzerland.
authors.forename: Anne
authors.initials: A
authors.lastname: Roller
authors.forename: Alessia
authors.initials: A
authors.lastname: Perino
authors.forename: Paolo
authors.initials: P
authors.lastname: Dapavo
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Soro
authors.forename: Klaus
authors.initials: K
authors.lastname: Okkenhaug
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.forename: Hong
authors.initials: H
authors.lastname: Ji
mesh_terms: D000634:Aminoquinolines / Q000633:toxicity*; D000818:Animals; D058534:Class I Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000502:physiology; D003872:Dermatitis / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D005260:Female; D055879:Gene Knock-In Techniques; D006801:Humans; D000077271:Imiquimod; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000097:blood; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011565:Psoriasis / Q000139:chemically induced / Q000276:immunology* / Q000628:therapy*; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology / Q000473:pathology
chemical_list: D000634:Aminoquinolines; D058534:Class I Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; D000077271:Imiquimod; D020381:Interleukin-17; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; C421683:Pik3cd protein, mouse; C546764:Pik3cg protein, mouse