Spleen tyrosine kinase inhibition in the treatment of autoimmune, allergic and autoinflammatory diseases

Pamuk, Ömer Nurı; Tsokos, George C.

doi:10.1186/ar3198

Cited by 71 publications

(65 citation statements)

References 64 publications

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“…These observations open the possibility that IL-21, in mononuclear cells, exerts functions other than phagocytosis, which involve the participation of Syk, an enzyme that is becoming recognized to play crucial roles in several biological functions (40). Moreover, knowing that targeting Syk is relevant to the treatment of inflammatory diseases (41)(42)(43), and because IL-21 is associated with a variety of inflammatory disorders, including psoriasis, systemic lupus erythematosus, and arthritis (44)(45)(46), our results support the targeting of the IL-21/IL-21R system for the development of therapeutic strategies.…”

Section: Discussionmentioning

confidence: 99%

IL-21 Enhances Phagocytosis in Mononuclear Phagocyte Cells: Identification of Spleen Tyrosine Kinase as a Novel Molecular Target of IL-21

Vallières

Girard

2013

The Journal of Immunology

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The biological significance of the IL-21/IL-21R system in human monocytes/macrophages is not well documented, and the expression of IL-21R is unclear and has been disputed. In this study, we showed for the first time, to our knowledge, that human monocyte–like THP-1 cells expressed the two IL-21R components, CD132 (γc) and IL-21Rα, on their cell surface, as assessed by flow cytometry. Moreover, IL-21 was found to enhance FcR-mediated phagocytosis, but not endocytosis. The ability of IL-21 to enhance phagocytosis was not associated with an increased expression of both IL-21R components at the cell surface, and IL-21 did not act in synergy with IL-15. IL-21 activated spleen tyrosine kinase (Syk), as evidenced by its ability to increase Syk phosphorylation. Using a pharmacological approach to inhibit Syk activity, and an antisense technique to downregulate Syk protein expression, we demonstrated the importance of Syk in IL-21–induced phagocytosis. In addition, both CD132 and IL-21Rα were expressed on the cell surface of naive monocytes, as well as in GM-CSF–monocyte-derived macrophages. Moreover, IL-21 also induced phagocytosis in these cells. We conclude that IL-21 possesses important biological effects in mononuclear phagocyte cells and that Syk is a novel molecular target of IL-21 that was previously unknown. Therefore, future development of therapeutic strategies targeting the IL-21/IL-21R system should consider that monocyte and macrophage cell physiology may be affected by this system.

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Section: Discussionmentioning

confidence: 99%

IL-21 Enhances Phagocytosis in Mononuclear Phagocyte Cells: Identification of Spleen Tyrosine Kinase as a Novel Molecular Target of IL-21

Vallières

Girard

2013

The Journal of Immunology

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“…Small-molecule inhibitors of SYK activity suppress disease in a number of inflammatory disease models. 76 SYK can be detected in the skin lesions of MRL/lpr mice, 77 and treatment with a SYK inhibitor can abrogate the development of skin lesions induced by intradermal injection of lupus IgG in MRL/lpr mice, as well as suppress established skin lesions in such mice. 77 In addition, inhibition of SYK can result in the disappearance of established skin lesions in BAK -/-BAX -/-double-knockout mice, which spontaneously develop inflammatory skin lesions.…”

Section: Sykmentioning

confidence: 99%

Pathogenesis and targeted treatment of skin injury in SLE

Deng

Tsokos

2015

Nat Rev Rheumatol

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Skin is the second most common organ (after the kidney) to be affected in patients with systemic lupus erythematosus (SLE), yet the aetiology of skin injury and the mechanisms involved in the development of dermal manifestations of SLE remain unclear. Ultraviolet light (UV), immune cells, cytokines and deposition of immunoglobulins all seem to have a role in the development of skin inflammation and damage in SLE. UV represents the most important environmental factor, and exposure to UV triggers the development of skin lesions in areas where immunoglobulin has been deposited and various other components of the immune system have accumulated. In addition, a number of intracellular kinases and transcription factors have also been demonstrated to be involved in the generation of skin lesions in lupus-prone mice. These molecules can be targeted by small-molecule inhibitors, leading to the prospect that treatments suitable for topical application, and with limited adverse effects, could be developed. Further studies to eliminate the burden of skin inflammation in patients with SLE are clearly required.

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“…21 Furthermore, the selectivity of R406 for Syk is open to question because it inhibits multiple tyrosine kinases. 21,22 Similarly, the lack of a selective pharmacologic agent with favorable pharmacokinetic properties has limited the evaluation of Syk kinase activity in atherogenesis and restenosis.…”

Section: Introductionmentioning

confidence: 99%

Critical role for Syk in responses to vascular injury

André

Morooka

Sim

et al. 2011

Blood

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Although current antiplatelet therapies provide potent antithrombotic effects, their efficacy is limited by a heightened risk of bleeding and failure to affect vascular remodeling after injury. New lines of research suggest that thrombosis and hemorrhage may be uncoupled at the interface of pathways controlling thrombosis and inflammation. Here, as one remarkable example, studies using a novel and highly selective pharmacologic inhibitor of the spleen tyrosine kinase Syk [PRT060318; 2-((1R,2S)-2-aminocyclohexylamino)-4-(m-tolylamino)pyrimidine-5-carboxamide] coupled with genetic experiments, demonstrate that Syk inhibition ameliorates both the acute and chronic responses to vascular injury without affecting hemostasis. Specifically, lack of Syk (murine radiation chimeras) attenuated shear-induced thrombus formation ex vivo, and PRT060318 strongly inhibited arterial thrombosis in vivo in multiple animal species while having minimal impact on bleeding. Furthermore, leukocyte-platelet–dependent responses to vascular injury, including inflammatory cell recruitment and neointima formation, were markedly inhibited by PRT060318. Thus, Syk controls acute and long-term responses to arterial vascular injury. The therapeutic potential of Syk may be exemplary of a new class of antiatherothrombotic agents that target the interface between thrombosis and inflammation.

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Spleen tyrosine kinase inhibition in the treatment of autoimmune, allergic and autoinflammatory diseases

Cited by 71 publications

References 64 publications

IL-21 Enhances Phagocytosis in Mononuclear Phagocyte Cells: Identification of Spleen Tyrosine Kinase as a Novel Molecular Target of IL-21

IL-21 Enhances Phagocytosis in Mononuclear Phagocyte Cells: Identification of Spleen Tyrosine Kinase as a Novel Molecular Target of IL-21

Pathogenesis and targeted treatment of skin injury in SLE

Critical role for Syk in responses to vascular injury

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