Tyrosine kinase is an important enzyme. Its activity is linked to the phosphorylation of multiple cellular proteins required for cell functions [Citation1]. One of such functions is cell migration. Eosinophil is the chief inflammatory cell recruited to the nasal tissue in allergic rhinitis (AR) and eosinophilic chronic rhinosinusitis (CRS). Hence, signal transduction mechanisms involved in eosinophil migration against concentration gradients (chemotaxis) of allergic and inflammatory mediators (chemokines) are of great interest.
For a cell to migrate the ligand–receptor interaction results in rapid signal transduction mediated by kinases activation with increase in F-actin content and cytoskeletal changes [Citation2,Citation3]. Tyrosine kinase is one of these kinases that is known to be involved in eosinophil chemotaxis signal transduction. However, whether tyrosine kinase activity is also linked to eosinophil receptor gene expression is still unclear.
We have recently shown that the gene expression of CRTH2, the chemoattractant receptor-homologous molecule expressed by TH2 cells and eosinophils, requires inhibition of the tyrosine kinase activity [Citation4]. This is a novel finding indicating the importance of the balance between tyrosine kinase and tyrosine phosphatase activity in health and disease, and highlighting tyrosine kinase functions as an ‘on’ or ‘off’ switch in many cellular functions.
For example, while some important eosinophilsʼ receptor, such as CCR3, involved in chemotaxis is linked to tyrosine kinase activation or ‘on-switch’ resulting in eotaxin-induced eosinophil chemotaxis [Citation5], other receptors’ gene expression is modulated by tyrosine kinase inhibition or ‘off-switch’, such as CRTH2 receptor [Citation5], also resulting in prostaglandin D2 and/or vasoactive intestinal peptide-induced eosinophil chemotaxis.
In nasal inflammation, whether allergic or non-allergic, there is a pool of mediators released in the inflammatory site. Interaction of these mediators with their specific receptors on the surface of eosinophil may activate or deactivate tyrosine kinases and phosphatases resulting in nasal eosinophilia. The fact that several tyrosine kinase inhibitors were effectively able to upregulate the gene expression of CRTH2 [Citation4] supports this hypothesis.
Research focusing on exploring which specific tyrosine kinase(s) switch off activity involved in CRTH2 receptor gene regulation is required. Whether there is/are receptor tyrosine kinase(s) involved physically in a compartmental complex with CRTH2 should also be explored.
Tyrosine kinase activity and eosinophil migration is a current topic of interest that needs to be more explored in relation to receptor gene expression regulation. Further investigations in this area will result in a better understanding of the complex mechanism involved in the schizophrenic behavior of eosinophil chemotaxis to tyrosine kinase(s) ‘on’ and ‘off’ switch activating pattern.
Disclosure statement
No potential conflict of interest was reported by the author.
References
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- Bacon KB, Szabo MC, Yssel H, et al. RANTES induces tyrosine kinase activityof stably complexed p125FAK and ZAP-70 in human T cells. J Exp Med. 1996;184:873–882.
- Knall C, Worthen GS, Johnson GL. Interleukin 8-stimulated phosphatidylinositol-3-kinase activity regulates the migration of human neutrophils independent of extracellular signal-regulated kinase and p38 mitogen-activated protein kinases. Proc Natl Acad Sci U S A. 1997;94:3052–3057.
- El-Shazly AE, Roncarati P, Lejeune M, et al. Tyrosine kinase inhibition is an important factor for gene expression of CRTH2 in human eosinophils and lymphocytes: A novel mechanism for explaining eosinophils recruitment by the neuro-immune axis in allergic rhinitis. Int Immunopharmacol. 2017;45:180–186.
- El-Shazly N, Yamaguchi K, Masuyama T, et al. Novel Association of the Src- Family kinases with CCR3 receptor stimulation: A possible mechanism for eotaxin-induced human eosinophil chemotaxis. Biochem Biophys Res Commun. 1999;264:163–170.