Expression and Role of the TrkA Receptor in Pulmonary Inflammatory Diseases

Abstract

The nerve growth factor NGF belongs to the neurotrophin family and was described for the first time more than fifty years ago by Rita Levi-Montalcini and collaborators (LeviMontalcini et al., 1995; Levi-Montalcini & Hamburger, 1951), who showed its major role in neuronal growth and survival. NGF effects are mediated by activation of two receptor types: the low-affinity p75 receptor for neurotrophins (p75NTR) and the high-affinity tropomyosinrelated kinase A (TrkA) receptor (Freund-Michel & Frossard, 2008a). The p75NTR receptor belongs to the death receptor family and its activation by NGF at nanomolar concentrations leads either to proor anti-apoptotic signalling pathways. The p75NTR receptor is not selective for NGF as it can also bind pro-neurotrophins and the other neurotrophins at the same nanomolar concentrations (Chao, 2003). Inversely, the TrkA receptor is selective for NGF and belongs to the tyrosine-kinase receptor family. Its activation by NGF at picomolar concentrations activates signalling pathways inducing cell proliferation, differentiation and survival in particular through activation of phosphatidylinositol-3 kinase (PI3K), small protein G Ras, phospholipase C (PLC) and mitogen-activated protein kinases (MAPK) (Freund-Michel & Frossard, 2008a). The role of NGF in neuronal growth and survival has been widely studied and led to consider NGF as a promising therapeutic target in several pathologies of the nervous system, in particular neurodegenerative diseases (Prakash et al., 2010). In addition, many studies have suggested that NGF also plays the role of an inflammatory mediator, in particular in the lung (Freund-Michel & Frossard, 2008a). Indeed, numerous sources of NGF have been described in the lung, including infiltrated inflammatory cells, sensory nerves, and many lung structural cells such as fibroblasts, epithelial, endothelial, and