Characterization of inducible SYK knockout mice

Abstract

Spleen tyrosine kinase (SYK), a cytoplasmic non-receptor tyrosine kinase, is a key mediator of immunoreceptor signalling. SYK is expressed in cells of the hematopoietic lineage such as B cells, mast cells, basophils, neutrophils, macrophages, and osteoclasts, but is also present in cells of non-hematopoietic origin such as epithelial cells, hepatocytes, fibroblasts, neuronal cells, and vascular endothelial cells. Thus, SYK appears to play a general physiological function in a wide variety of cells. SYK functions downstream of ITAM-containing antigen- and Fc-receptor complexes and transduces signals leading to a host of effector functions including altered gene expression, cytokine production, cell differentiation and proliferation. Since SYK signalling downstream of the B cell receptor is necessary for B cell development and maturation, SYK is discussed as a candidate for the treatment of certain B cell lymphomas, which are characterized by uncontrolled SYK-dependent growth, like the B cell non-Hodgkin lymphoma. Abnormal signalling through SYK is further associated with different antibody-mediated autoimmune diseases and allergic disorders including rheumatoid arthritis, asthma and allergic rhinitis, making SYK an attractive pharmacological target for the treatment of these diseases. Due to the involvement of SYK in numerous diseases with high unmet medical need extensive efforts have been made to further characterize the role of SYK in preclinical models in vivo. Since conventional germ-line deleted SYK knockout mice suffer from severe haemorrhaging and die perinatally efforts to generate a mouse model allowing the characterization of SYK have been unsuccessful. To circumvent these difficulties, a tamoxifen-inducible SYK knockout strain was generated, allowing to knockout SYK in adult mice and thus to evaluate the effect of SYK deletion on physiological parameters and in various disease-related animal models. Short-term SYK deletion had no negative impact on health status of adult mice. After long-term SYK deletion reduced B cell counts and slight improvements on bone morphology were observed. SYK deletion proved to be efficacious in mast cell-driven animal models including a model of passive cutaneous anaphylaxis and a model of ovalbumin-induced lung eosinophilia. However, SYK deletion did not impact the migration of neutrophils or macrophages after the application of inflammatory stimuli including lipopolysaccharid, thioglycollate, cigarette smoke or MCP-1. As such, the tamoxifen-inducible SYK knockout mice provide a appropriate tool to examine the role of SYK in various disease-related animal models.