title: Inhibition of TYK2 and JAK1 ameliorates imiquimod-induced psoriasis-like dermatitis by inhibiting IL-22 and the IL-23/IL-17 axis.
abstract: Psoriasis is a chronic autoimmune disease affecting the skin and characterized by aberrant keratinocyte proliferation and function. Immune cells infiltrate the skin and release proinflammatory cytokines that play important roles in psoriasis. The Th17 network, including IL-23 and IL-22, has recently emerged as a critical component in the pathogenesis of psoriasis. IL-22 and IL-23 signaling is dependent on the JAK family of protein tyrosine kinases, making JAK inhibition an appealing strategy for the treatment of psoriasis. In this study, we report the activity of SAR-20347, a small molecule inhibitor with specificity for JAK1 and tyrosine kinase 2 (TYK2) over other JAK family members. In cellular assays, SAR-20347 dose dependently (1 nM-10 μM) inhibited JAK1- and/or TYK2-dependent signaling from the IL-12/IL-23, IL-22, and IFN-α receptors. In vivo, TYK2 mutant mice or treatment of wild-type mice with SAR-20347 significantly reduced IL-12-induced IFN-γ production and IL-22-dependent serum amyloid A to similar extents, indicating that, in these models, SAR-20347 is probably acting through inhibition of TYK2. In an imiquimod-induced psoriasis model, the administration of SAR-20347 led to a striking decrease in disease pathology, including reduced activation of keratinocytes and proinflammatory cytokine levels compared with both TYK2 mutant mice and wild-type controls. Taken together, these data indicate that targeting both JAK1- and TYK2-mediated cytokine signaling is more effective than TYK2 inhibition alone in reducing psoriasis pathogenesis.
authors.affiliation: Biosciences Division, Center for Immunology and Infectious Diseases, SRI International, Menlo Park, CA 94025; and.
authors.forename: Melissa G
authors.initials: MG
authors.lastname: Works
authors.affiliation: Biosciences Division, Center for Immunology and Infectious Diseases, SRI International, Menlo Park, CA 94025; and.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Yin
authors.affiliation: Biosciences Division, Center for Immunology and Infectious Diseases, SRI International, Menlo Park, CA 94025; and.
authors.forename: Catherine C
authors.initials: CC
authors.lastname: Yin
authors.affiliation: Biosciences Division, Center for Immunology and Infectious Diseases, SRI International, Menlo Park, CA 94025; and.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yiu
authors.affiliation: Biosciences Division, Center for Immunology and Infectious Diseases, SRI International, Menlo Park, CA 94025; and.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Shew
authors.affiliation: Biosciences Division, Center for Immunology and Infectious Diseases, SRI International, Menlo Park, CA 94025; and.
authors.forename: Thanh-Thuy
authors.initials: TT
authors.lastname: Tran
authors.affiliation: Biosciences Division, Center for Immunology and Infectious Diseases, SRI International, Menlo Park, CA 94025; and.
authors.forename: Nahoko
authors.initials: N
authors.lastname: Dunlap
authors.affiliation: Biosciences Division, Center for Immunology and Infectious Diseases, SRI International, Menlo Park, CA 94025; and.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lam
authors.affiliation: Sareum, Cambridge CB22 3FX, United Kingdom.
authors.forename: Tim
authors.initials: T
authors.lastname: Mitchell
authors.affiliation: Sareum, Cambridge CB22 3FX, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Reader
authors.affiliation: Biosciences Division, Center for Immunology and Infectious Diseases, SRI International, Menlo Park, CA 94025; and.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Stein
authors.affiliation: Biosciences Division, Center for Immunology and Infectious Diseases, SRI International, Menlo Park, CA 94025; and annalisa.dandrea@sri.com.
authors.forename: Annalisa
authors.initials: A
authors.lastname: D'Andrea
mesh_terms: D000818:Animals; D003872:Dermatitis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology*; D053759:Interleukin-23 / Q000235:genetics / Q000276:immunology*; D007378:Interleukins / Q000235:genetics / Q000276:immunology*; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011565:Psoriasis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D000685:Serum Amyloid A Protein / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D053634:TYK2 Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D000097043:Interleukin-22
chemical_list: D007371:Interferon-gamma; D018664:Interleukin-12; D020381:Interleukin-17; D053759:Interleukin-23; D007378:Interleukins; D053613:Janus Kinase 1; D047428:Protein Kinase Inhibitors; D000685:Serum Amyloid A Protein; D053634:TYK2 Kinase; D000097043:Interleukin-22; C573415:IFNG protein, human; C507904:JAK1 protein, human; C507905:Jak1 protein, mouse; C070139:TYK2 protein, human; C499356:Tyk2 protein, mouse