Nerve growth factor and its role in immunoinflammatory and endocrine metabolic diseases

Ildikó Molnár

Immunoendocrinology, EndoMed, Debrecen 

Correspondence: Ildikó Molnár, Immunoendocrinology, EndoMed, Debrecen, Bem tér 18/C., H-4026 Debrecen, Hungary, Email [email protected]

 Received: November 22, 2023                                                                                                           Published: December 09, 2023 

Citation: Molnar I. Nerve growth factor and its role in immuno-inflammatory and endocrine-metabolic diseases. AOJ Emerg and Int Med. 2023;1(2):01–08. 

Copyright: ©2023 Molnár. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and build upon your work non-commercially

Abstract 

NGF is a neurotrophin essential for the maintenance, differentiation and growth of peripheral sympathetic and sensory neurons. The regulation of NGF and its secretion in allergy, Graves’ ophthalmopathy, obesity and menopausal metabolic changes such as osteoporosis may provide new perspectives for their therapeutic approach. NGF plays a crucial non-neural regulatory role in immune and hematopoietic cells, modifying inflammatory processes and self-secretion. Local sympathetic and sensory neuronal activity could be enhanced by the release of active mediators, cytokines and active peptides from mast cells in allergic diseases. NGF is involved in the development of Th2 dominance, hypertrophy and apoptosis in Graves’ ophthalmopathy. Pancreatic beta cells are the source of insulin synthesis and secretion. NGF co-secretion with insulin has been demonstrated in response to glucose levels. Obesity and postmenopause are associated with increased sympathetic activity and a greater tendency to develop increased insulin resistance, type 2 diabetes mellitus and metabolic syndrome. The specific neuronal action of NGF is to modulate nociception by altering receptor sensitization, gene expression and local neuronal sprouting associated with chronic pain, neuropathic pain, fibromyalgia and cancer pain. Several anti-NGF antibody therapies are available and have shown some success. 

Keywords: nerve growth factor, chronic pain, allergy, Graves’ ophthalmopathy, obesity, menopausal osteoporosis

Introduction 

Nerve growth factor (NGF) is one of the four neurotrophic factors [brain-derived neurotrophic factor (BDNF), neurotrophin-3 and neurotrophin-4/5]. NGF is essential for the maintenance, differentiation and growth of peripheral sympathetic and sensory neurons and basal forebrain cholinergic neurons. Its neuronal origin and role is characterized by the modulation of nociception by altering receptor sensitization, gene expression and local neuronal sprouting. 1 In turn, NGF is characterized by a broad spectrum of non-neuronal regulatory effects showing interactions with immune-hematopoietic (T and B lymphocytes, monocytes/macrophages, eosinophils, basophils, neutrophils), parenchymal cells (adipocytes, pancreatic beta cells, thyrocytes, keratinocytes, osteoblasts, mesenchymal cells) and structural cells (fibroblasts, vascular stromal cells).2 Two NGF receptors are known, a high-affinity, tropomyosin-related receptor with tyrosine kinase A activity (TrkA) and a low-affinity p75 receptor (p75NTR).3,4 NGF is synthesized from proNGF after intracellular enzymatic cleavage by furin or extracellular enzymatic cleavage by plasmin or matrix metalloproteinases. The TrkA receptor activates three major signaling cascades: the mitogen-activated protein kinase (MAPK/ERK) pathway, the phospholipase C-γ (PLC γ) pathway and the phosphoinositide 3-kinase (PI3K) pathway. These pathways are responsible for proliferation, cell differentiation, synaptic plasticity and survival. p75NTR activation induces an apoptotic signaling pathway with caspase 3, 6 and 9 activities.5 The expression of TrkA and p75NTR is cell specific and depends on local levels of NGF, inflammatory cytokines and drugs. NGF-null mice showed severe loss of sympathetic and sensory neurons, particularly peptidergic small and medium diameter dorsal root ganglion (DRG) neurons.6 Hereditary sensory and autonomic neuropathy type V (HSAN V) is caused by a point mutation of the NGF gene at nucleotide 661, cytosine to thymine.7 The mutation reduces sensitivity to cold and heat, but sweating remains normal. The mutation at nucleotide 680 (cytosine to adenosine) resulted in complete insensitivity to pain with anhydrosis, mild mental retardation and immune deficiency.8