Spleen tyrosine kinase (SYK) is known to have a crucial role in adaptive immune receptor signalling. However, recent reports indicate that SYK also mediates other, unexpectedly diverse biological functions, including cellular adhesion, innate immune recognition, osteoclast maturation, platelet activation and vascular development. SYK is activated by C-type lectins and integrins, and activates new targets, including the CARD9-BCL-10-MALT1 pathway and the NLRP3 inflammasome. Studies using Drosophila melanogaster suggest that there is an evolutionarily ancient origin of SYK-mediated signalling. Moreover, SYK has a crucial role in autoimmune diseases and haematological malignancies. This Review summarizes our current understanding of the diverse functions of SYK and how this is being translated for therapeutic purposes.

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The SYK tyrosine kinase: a crucial player in diverse biological functions.

Immunocompromised individuals are at high risk from fungal infection, yet the molecular mechanisms that govern host defence against fungi are not well understood. Gross et al. now show that Candida albicans infection in mice activates the NALP3 inflammasome via a mechanism involving Sky-induced production of reactive oxygen induced by the tyrosine kinase Syk.

Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence.

A gene expression signature associated with “K-Ras addiction” reveals regulators of EMT and tumor cell survival

Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia

In inflammatory conditions such as RA, the neutrophil has tended to be dismissed as a short-lived, terminally differentiated, irrelevant bystander cell. However, this is clearly not the case. A better understanding of the complex heterogeneous pathways and processes that constitute RA, in parallel with a more sophisticated knowledge of neutrophil biology has identified many potential roles for these cells in the persistence of inflammation and progression of joint damage, which should not be underestimated. Not only are neutrophils found in high numbers within the rheumatoid joint, both in synovial tissue and in joint fluid, they have a huge potential to directly inflict damage to tissue, bone and cartilage via the secretion of proteases and toxic oxygen metabolites, as well as driving inflammation through antigen presentation and secretion of cytokines, chemokines, prostaglandins and leucotrienes. Drugs already used to treat RA down-regulate many neutrophil functions, including migration to the joint, degranulation and production of inflammatory mediators, and these cells should be considered as important targets for the development of new therapies in the future.

/pdf/neutrophil-function-in-inflammation-and-inflammatory-3d4j7ltn91.pdf

Neutrophil function in inflammation and inflammatory diseases

Recent compelling evidence has lead to renewed interest in the role of antibodies and immune complexes in the pathogenesis of several autoimmune disorders, such as rheumatoid arthritis. These immune complexes, consisting of autoantibodies to self-antigens, can mediate inflammatory responses largely through binding and activating the immunoglobulin Fc receptors (FcRs). Using cell-based structure activity relationships with cultured human mast cells, we have identified the small molecule R406 [ N 4-(2,2-dimethyl-3-oxo-4 H -pyrid[1,4]oxazin-6-yl)-5-fluoro- N 2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine] as a potent inhibitor of immunoglobulin E (IgE)- and IgG-mediated activation of Fc receptor signaling (EC 50 for degranulation = 56–64 nM). Here we show that the primary target for R406 is the spleen tyrosine kinase (Syk), which plays a key role in the signaling of activating Fc receptors and the B-cell receptor (BCR). R406 inhibited phosphorylation of Syk substrate linker for activation of T cells in mast cells and B-cell linker protein/SLP65 in B cells. R406 bound to the ATP binding pocket of Syk and inhibited its kinase activity as an ATP-competitive inhibitor ( K i = 30 nM). Furthermore, R406 blocked Syk-dependent FcR-mediated activation of monocytes/macrophages and neutrophils and BCR-mediated activation of B lymphocytes. R406 was selective as assessed using a large panel of Syk-independent cell-based assays representing both specific and general signaling pathways. Consistent with Syk inhibition, oral administration of R406 to mice reduced immune complex-mediated inflammation in a reverse-passive Arthus reaction and two antibody-induced arthritis models. Finally, we report a first-inhuman study showing that R406 is orally bioavailable, achieving exposures capable of inhibiting Syk-dependent IgE-mediated basophil activation. Collectively, the results show R406 potential for modulating Syk activity in human disease.

https://jpet.aspetjournals.org/content/jpet/early/2006/08/31/jpet.106.109058.full.pdf

Scott Lovell

Papers

R406, an Orally Available Spleen Tyrosine Kinase Inhibitor Blocks Fc Receptor Signaling and Reduces Immune Complex-Mediated Inflammation