Tyk2 is a therapeutic target for psoriasis-like skin inflammation

Ishizaki, Masayuki; Muromoto, Ryuta; Akimoto, Toshihiko; Sekine, Yoshifumi; Kawa, Shigeyuki; Diwan, Manish; Maeda, Hiroaki; Togi, Sumihito; Shimoda, Kazuya; Oritani, Kenji; Matsuda, Tadashi

doi:10.1093/intimm/dxt062

Cited by 72 publications

(66 citation statements)

References 52 publications

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“…3). Previous reports demonstrated a requirement of Tyk2 for fullfledged STAT3 activation upon inflammation for lymphoid tissues (4) and keratinocytes (5). As expected (8), the expression of the major STAT3-activating cytokines IL-6 and IL-22 was elevated during colitis, albeit with no genotype differences that could account for the impaired pY-STAT3 in Tyk2 2/2 mice (Fig.…”

Section: Discussionsupporting

confidence: 70%

“…Genome-wide association studies identified Tyk2 as susceptibility locus for IBD in humans (41). During inflammation, Tyk2 2/2 mice show opposing phenotypes in that they are either protected from Th1-or Th17-driven diseases (4,5,42,43) or more prone to Th2-or Th9-dominated pathology (2, 3).…”

Section: Discussionmentioning

confidence: 99%

“…Owing to their altered Th1/Th2, Th9, and Th17 cytokine profiles, these mice are more prone to allergic airway inflammation (2,3). Alternatively, Tyk2-null mice are more resistant to autoimmune diseases (4,5). In humans, Tyk2 deficiency has been demonstrated to affect signaling of type I IFNs, IL-6, IL-10, IL-12, and IL-23, leading to increased susceptibility to infections and inflammatory symptoms (6,7).…”

mentioning

confidence: 99%

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Intestinal Epithelial Cell Tyrosine Kinase 2 Transduces IL-22 Signals To Protect from Acute Colitis

Hainzl

Stockinger

Rauch

et al. 2015

The Journal of Immunology

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In the intestinal tract, IL-22 activates STAT3 to promote intestinal epithelial cell (IEC) homeostasis and tissue healing. The mechanism has remained obscure, but we demonstrate that IL-22 acts via tyrosine kinase 2 (Tyk2), a member of the Jak family. Using a mouse model for colitis, we show that Tyk2 deficiency is associated with an altered composition of the gut microbiota and exacerbates inflammatory bowel disease. Colitic Tyk2−/− mice have less p-STAT3 in colon tissue and their IECs proliferate less efficiently. Tyk2-deficient primary IECs show reduced p-STAT3 in response to IL-22 stimulation, and expression of IL-22–STAT3 target genes is reduced in IECs from healthy and colitic Tyk2−/− mice. Experiments with conditional Tyk2−/− mice reveal that IEC-specific depletion of Tyk2 aggravates colitis. Disease symptoms can be alleviated by administering high doses of rIL-22–Fc, indicating that Tyk2 deficiency can be rescued via the IL-22 receptor complex. The pivotal function of Tyk2 in IL-22–dependent colitis was confirmed in Citrobacter rodentium–induced disease. Thus, Tyk2 protects against acute colitis in part by amplifying inflammation-induced epithelial IL-22 signaling to STAT3.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Intestinal Epithelial Cell Tyrosine Kinase 2 Transduces IL-22 Signals To Protect from Acute Colitis

Hainzl

Stockinger

Rauch

et al. 2015

The Journal of Immunology

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“…Although we cannot show a significant difference between the groups this is still intriguing since TYK2 is part of the IL-23 pathway which seems preferentially involved in the severe psoriasis phenotype and inhibition of Tyk2 kinase activity lead to significantly reduced IL-23-induced skin inflammation and may be an effective therapeutic strategy for the treatment of psoriasis (Ishizaki et al, 2014;Liang et al, 2013).…”

Section: Discussionmentioning

confidence: 64%

Association with Genetic Variants in the IL-23 and NF-κB Pathways Discriminates between Mild and Severe Psoriasis Skin Disease

Nikamo

Lysell

Ståhle

2015

Journal of Investigative Dermatology

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Psoriasis is clinically heterogeneous, and symptoms can vary from mild almost cosmetic symptoms to severe disease requiring systemic therapy. Biomarkers predicting disease development are lacking. Herein we explored the genetic background in two polarized cohorts of carefully phenotyped patients with long-term follow-up: consistent mild phenotype (n=696) and severe disease course requiring systemic therapy (n=715). All patients were treated at the same dermatology department ensuring homogenous assessment. Genotyping included known psoriasis-associated variants, with special focus on the IL-23 and NF-κB pathways. A case-case study comparing severe and mild psoriasis phenotypes, controlling for age at disease onset and gender, revealed significant differences between the two groups for SNPs in IL23R, NFKB1, IL21, IL12B, NFKBIL1 and IL23A. HLA-C*06 associated equally in the mild and severe disease cohorts. Strong additive effects when combining HLA-C*06 with IL23A, IL23R, IL12B, NFKB1 or TNIP1 were restricted to the severe cohort, indicating that activation of these pathways may influence disease severity in psoriasis. No protective gene was identified in the mild cohort, suggesting that current screens have primarily identified psoriasis variants associated with a more severe phenotype. These results demonstrate the importance of careful phenotyping and long-term clinical follow-up in genetic studies.

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“…13,14 The first TYK2 specific inhibitors have been recently developed and are considered as promising therapeutic agents for the treatment of inflammatory and autoimmune diseases. [15][16][17][18][19][20] Very recently, tumor cell-intrinsic TYK2 activity has been linked to the development of T cell acute lymphoblastic leukemia (T-ALL) and cutaneous T cell lymphoma development in humans. 21,22 Therefore, specific inhibition of TYK2 activity might be considered as a new therapeutic opportunity for some hematologic malignancies.…”

Section: Introductionmentioning

confidence: 99%

In vivo tumor surveillance by NK cells requires TYK2 but not TYK2 kinase activity

et al. 2015

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Abbreviations: CCL3, chemokine (C-C motif) ligand 3; CFSE, carboxyfluorescein diacetate succinimidyl ester; GzmB, granzyme B; IFN, interferon; IFNAR, interferon a and b receptor; IL, interleukin; IL-12Rb1, interleukin-12 receptor subunit b-1; iNK, immature natural killer; JAK, xJanus kinase; MACS, magnetic-activated cell sorting; MFI, mean fluorescence intensity; MHC, major histocompatibility complex; miR, microRNA; mNK, mature natural killer; NK, natural killer; NKP, natural killer precursor; Prf1, perforin; SEM, standard error of the mean; STAT, signal transducer and activator of transcription; T-ALL, T cell acute lymphoblastic leukemia; TYK2, tyrosine kinase 2; TYK2 K923E , kinase-inactive tyrosine kinase 2; WT, wild-typeTyrosine kinase 2 (TYK2) is a Janus kinase (JAK) that is crucially involved in inflammation, carcinogenesis and defense against infection. The cytotoxic activity of natural killer (NK) cells in TYK2-deficient (Tyk2 ¡/¡ ) mice is severely reduced, although the underlying mechanisms are largely unknown. Using Tyk2 ¡/¡ mice and mice expressing a kinase-inactive version of TYK2 (Tyk2 K923E ), we show that NK cell function is partly independent of the enzymatic activity of TYK2. Tyk2 ¡/¡ and Tyk2 K923E NK cells develop normally in the bone marrow, but the maturation of splenic Tyk2 ¡/¡ NK cells (and to a lesser extent of Tyk2 K923E NK cells) is impaired. In contrast, the production of interferon g (IFNg) in response to interleukin 12 (IL-12) or to stimulation through NK cell-activating receptors strictly depends on the presence of enzymatically active TYK2. The cytotoxic activity of Tyk2 K923E NK cells against a range of target cells in vitro is higher than that of Tyk2 ¡/¡ NK cells. Consistently, Tyk2 K923E mice control the growth of NK cell-targeted tumors significantly better than TYK2-deficient mice, showing the physiological relevance of the finding. Inhibitors of TYK2's kinase activity are being developed for the treatment of inflammatory diseases and cancers, but their effects on tumor immune surveillance have not been investigated. Our finding that TYK2 has kinase-independent functions in vivo suggests that such inhibitors will leave NK cell mediated tumor surveillance largely intact and that they will be suitable for use in cancer therapy.

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Tyk2 is a therapeutic target for psoriasis-like skin inflammation

Cited by 72 publications

References 52 publications

Intestinal Epithelial Cell Tyrosine Kinase 2 Transduces IL-22 Signals To Protect from Acute Colitis

Intestinal Epithelial Cell Tyrosine Kinase 2 Transduces IL-22 Signals To Protect from Acute Colitis

Association with Genetic Variants in the IL-23 and NF-κB Pathways Discriminates between Mild and Severe Psoriasis Skin Disease

In vivo tumor surveillance by NK cells requires TYK2 but not TYK2 kinase activity

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