**Role of TrkA Receptor in Inflammation**

72 Inflammatory Diseases – A Modern Perspective

Xue, M., March, L., Sambrook, P.N., & Jackson, C.J. (2007). Differential regulation of matrix

Xue, M., Minhas, N., Chow, S.O., Dervish, S., Sambrook, P.N., March, L., & Jackson, C.J.

Xue, M., Thompson, P., Kelso, I., & Jackson, C. (2004). Activated protein C stimulates

Xue, M., Campbell, D., & Jackson, C.J. (2007). Protein C is an autocrine growth factor for human skin keratinocytes. *J. Biol. Chem.* Vol.282, No.18, pp. 13610-13616 Yamauchi, T., Sakurai, M., Abe, K., Takano, H., & Sawa, Y. (2006). Neuroprotective effects of

Yang, X.V., Banerjee, Y., Fernandez, J.A., Deguchi, H., Xu, X., Mosnier, L.O., Urbanus, R.T.,

Yuda, H., Adachi, Y., Taguchi, O., Gabazza, E.C., Hataji, O., Fujimoto, H., Tamaki, S.,

Yuksel, M., Okajima, K., Uchiba, M., Horiuchi, S., & Okabe, H. (2002). Activated protein C

Zhong, Z., Ilieva, H., Hallagan, L., Bell, R., Singh, I., Paquette, N., Thiyagarajan, M., Deane,

Zlokovic, B.V. (2005). Neurovascular mechanisms of Alzheimer's neurodegeneration. *Trends* 

Zlokovic, B.V. & Griffin, J.H. (2011). Cytoprotective protein C pathways and implications for stroke and neurological disorders. *Trends Neurosci.* Vol.34, No.4, pp. 198-209

spinal cord ischemia in rabbits. *Stroke.* Vol.37, No.4, pp. 1081-1086

cells. *Proc. Nat. Acad. Sci. U.S.A.* Vol.106, No.1, pp. 274-279

human monocytes. *Thromb.Haemost.* Vol.88, No.2, pp. 267-273

Vol.103, No.6, pp. 2196-2204

*Neurosci.* Vol.28, No.4, pp. 202-208

endothelial cells. *Cell Mol Life Sci.* Vol.67, No.9, pp.1537-1546

pp. 2864-2874

119-127

3449

metalloproteinase 2 and matrix metalloproteinase 9 by activated protein C: relevance to inflammation in rheumatoid arthritis. *Arthritis Rheum.* Vol.56, No.9,

(2010). Endogenous protein C is essential for the functional integrity of human

proliferation, migration and wound closure, inhibits apoptosis and upregulates MMP-2 activity in cultured human keratinocytes. *Exp Cell Res.* Vol.299, No.1, pp.

activated protein C through induction of insulin-like growth factor-1 (IGF-1), IGF-1 receptor, and its downstream signal phosphorylated serine-threonine kinase after

de Groot, P.G., White-Adams, T.C., McCarty, O.J., & Griffin, J.H. (2009). Activated protein C ligation of ApoER2 (LRP8) causes Dab1-dependent signaling in U937

Nishikubo, K., Fukudome, K., D'Alessandro-Gabazza, C.N., Maruyama, J., Izumizaki, M., Iwase, M., Homma, I., Inoue, R., Kamada, H., Hayashi, T., Kasper, M., Lambrecht, B.N., Barnes, P.J., & Suzuki, K. (2004). Activated protein C inhibits bronchial hyperresponsiveness and Th2 cytokine expression in mice. *Blood.*

inhibits lipopolysaccharide-induced tumor necrosis factor-alpha production by inhibiting activation of both nuclear factor-kappa B and activator protein-1 in

R., Fernandez, J.A., Lane, S., Zlokovic, A.B., Liu, T., Griffin, J.H., Chow, N., Castellino, F.J., Stojanovic, K., Cleveland, D.W., & Zlokovic, B.V. (2009). Activated protein C therapy slows ALS-like disease in mice by transcriptionally inhibiting SOD1 in motor neurons and microglia cells. *J. Clin. Invest.* Vol.119, No.11, pp. 3437-

**5** 

**Expression and Role of the** 

**Inflammatory Diseases** 

*1INSERM U1045 "Centre de Recherche Cardio-thoracique de Bordeaux", Bordeaux 2University Bordeaux Segalen, Bordeaux 3UMR 7200 CNRS "Laboratoire d'Innovation* 

*4University of Strasbourg, Strasbourg* 

and Nelly Frossard3,4

 *Thérapeutique", Strasbourg* 

*France* 

**TrkA Receptor in Pulmonary** 

Véronique Freund-Michel1,2, Bernard Muller1,2

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 (Levi-Montalcini 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 pro- or 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)

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

**1. Introduction** 

(Freund-Michel & Frossard, 2008a).
