Role of NGF and its receptors in wound healing (Review)

Abstract

Wound healing is an important and complicated process that includes four highly integrated and overlapping phases, haemostasis, inflammation, proliferation and tissue remodelling. Nerve growth factor (NGF) was the first member of a family of neurotrophic factors to be discovered, and is an essential neurotrophic factor for the development and maintenance of the central and peripheral nervous systems. Several studies have proposed that NGF and its receptors, tropomyosin-related kinase receptor 1 and NGF receptor, are involved in the wound healing process, and are important components of the healing of several wounds both in vivo and in vitro. Topical application of NGF significantly promotes the healing of different types of wounds, including diabetic foot ulcers, pressure ulcers and corneal wounds. The present review summarizes the status of NGF and its receptors in current literature, and discusses data obtained in the last few years on the healing action of NGF in cutaneous, corneal and oral wounds.

Keywords: cornea; nerve growth factor; nerve growth factor receptor; oral cavity; skin; tropomyosin-related kinase receptor 1; wound healing.

Figure 1

NGF-mediated regulation of the NGFR and NTRK1 signaling pathways. NGF binds to the extracellular domain of NTRK1 with high affinity, resulting in dimerization of NTRK1 and activation of its intracellular kinase. NTRK1 signaling is best characterized by activation of the three main downstream signal transduction pathways, the MAPK/ERK, PI3K/Akt and PLC-γ signaling pathways, which results in the differentiation and survival of neurites. NGF binds to NGFR with low affinity. NGFR activation involves different molecular mechanisms in different types of cells and tissue environments, and exerts effects via the NF-κB, JNK and ceramide signaling pathways, resulting in apoptosis, survival and inflammation. Interactions of NGFR with sortilin allow the high-affinity binding of proNGF. Subsequent activation of the Ras/MAPK pathway results in apoptosis. Interactions of NGFR with Nogo-R and LINGO-1 play roles in the regulation of growth. Activation of RhoA by the displacement of Rho-GDI inhibits neurite outgrowth from postnatal sensory neurons and cerebellar neurons. NGF, nerve growth factor; NTRK1, tropomyosin-related kinase receptor 1; MAPK/ERK, mitogen-activated protein kinase/extracellular signal-regulated protein kinase; PI3K/Akt, phosphatidylinositol-3-kinase/serine protein kinase; PLC-γ, phospholipase C-γ; NF-κB, nuclear transcription factor-kappa B; JNK, Jun N-terminal kinase; CR, cysteine-rich; Nogo-R, Nogo receptor; LINGO-1, leucine-rich repeat and immunoglobulin-like domain-containing protein-1.