Syk: a novel target for treatment of inflammation in lung disease.
Spleen Tyrosine Kinase (Syk) is widely expressed in the immune system and functions in the transmission of inflammatory signals via ITAM-bearing cell surface receptors. The broad expression pattern and importance of Syk in regulating innate immunity and the inflammatory response have led to significant interest from the pharmaceutical industry to developing anti-Syk therapeutics for the treatment of inflammatory disorders such as allergic rhinitis and rheumatoid arthritis. While the function and regulation of Syk has been well-described in leukocytes, where its primary role is an early transducer of signaling following immunoreceptor engagement, Syk has recently been described in non-immune cells, such as the airway epithelium, that also play an important role in mediating the inflammatory response. This manuscript will focus on the expression and function of Syk in the context of inflammatory lung diseases, and review recent data that have demonstrated novel roles for Syk in airway epithelial cells, particularly its role in mediating the human rhinovirus (HRV) induced inflammatory response and viral cell entry. In addition, data describing the efficacy of novel Syk inhibitors in the management of inflammatory diseases in animal models and early clinical trials are also reviewed.
Sanderson
Michael P
MP
Division of Respirology and Multi-Organ Transplantation Programme, University Health Network, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Lau
Christine W
CW
Schnapp
Andreas
A
Chow
Chung-Wai
CW
D000631:Aminopyridines; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008173:Lung Diseases, Obstructive / Q000150:complications / Q000276:immunology* / Q000628:therapy / Q000821:virology; D009025:Morpholines; D010078:Oxazines / Q000627:therapeutic use; D010850:Picornaviridae Infections / Q000150:complications / Q000276:immunology* / Q000628:therapy / Q000821:virology; D011024:Pneumonia, Viral / Q000209:etiology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011725:Pyridines / Q000627:therapeutic use; D011743:Pyrimidines; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D012229:Rhinovirus / Q000472:pathogenicity / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D000072377:Syk Kinase; D014774:Virulence / Q000276:immunology; D053586:Virus Internalization
D000631:Aminopyridines; D000893:Anti-Inflammatory Agents; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; C510788:N4-(2,2-dimethyl-3-oxo-4H-pyrid(1,4)oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine; D010078:Oxazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D018799:Intercellular Adhesion Molecule-1; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C523665:fostamatinib