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

Spleen tyrosine kinase (Syk) is a cytoplasmic tyrosine kinase of 72 kDa and a member of the ZAP70 (ζ-chain-associated protein kinase of 70 kDa)/Syk family of the non-receptor-type protein tyrosine kinases (PTKs) [1,2] and contains two SRC homology 2 (SH2) domains and a kinase domain [3]. Syk is expressed in most hematopoietic cells, including B cells, immature T cells, mast cells, neutrophils, macrophages, and platelets [1,3,4], and is important in signal transduction in these cells [2,5].Syk plays an important role in signal transduction initiated by the classic immunoreceptors, including B-cell receptors (BCRs), Fc receptors, and the activating natural killer receptors [3,6,7]. Syk is associated mainly with ITAM (immunoreceptor tyrosine-based activation motif)-dependent pathways and affects early development and activation of B cells, mast cell degranulation, neutrophil and macrophage phagocytosis, and platelet activation [1,3,4]. Functional abnormalities of these cells are invariably associated with both autoimmune and allergic diseases. Although there have been many exciting developments in the treatment of these diseases, there are still serious limitations of the efficacy of the used drugs as they are associated with the development of serious side effects. Because of the central role of Syk in signaling processes not only in cells of the adaptive immune response but also in additional cell types known to be involved in the expression of tissue pathology in autoimmune, autoinflammatory, and allergic diseases, Syk inhibition has attracted considerable interest for further development. In this review, we will provide a brief account of the role of Syk signaling in various cell types and will summarize preclinical and clinical studies, which point to the therapeutic usefulness of Syk inhibition.The function of Src-family kinases and Syk kinases in immunoreceptor signaling pathways is well known (Figure 1) [6]. After receptor engagement, Src-family kinases phospho