Neurotrophins in Asthma

Abstract

Purpose of review: Asthma is a chronic airway disease that affects more than 300 million people worldwide. Current treatment focuses on symptomatic relief by temporally dampening inflammation and relaxing the airway. Novel combative strategies against asthma and hopefully a cure are yet to be developed. The goal of this review is to summarize recent literature on neurotrophins (NTs) in experimental models and clinical settings of asthma research.

Recent findings: We highlight studies of early phases of asthma that collectively reveal a profound impact of elevated NT levels following initial detrimental insults on long-term airway dysfunction. We hope this review will foster insights into the complex interaction between NTs, nerves, immune cells, and airway structural cells during a critical time window of development and disease susceptibility. Future studies are required to better understand the role of NTs in asthma pathophysiology and to evaluate whether NTs and their receptors may serve as new drug targets.

Keywords: Asthma; Brain-derived neurotrophic factor; Nerve growth factor; Neurotrophin 4; Neurotrophins.

Fig. 1

NTs and their receptors. NTs bind to respective high-affinity Trk receptors with relative specificity that triggers the activation of the PI3K/Akt and Ras/MAPK pathways and in turn, induces cell survival, proliferation, and differentiation. All four NTs also bind to a low-affinity p75NTR to induce apoptosis through the JNK pathway

Fig. 2

The expression of NTs and the Trk receptors in the lung. Airway epithelium, airway smooth muscle cells, and immune cells express NTs, including NGF, BDNF, and NT4. Nerves innervating the airway smooth muscle and pulmonary neuroendocrine cells (PNECs) express p75NTR and TrkA/B receptors. In addition, a variety of immune cells including macrophages, T cells, B cells, eosinophils, and mast cells express the TrkA receptor, which promote their survival, cytokine secretion, degranulation, and enhanced phagocytosis. TrkB expression is reported in primary human airway smooth muscle cells in culture

Fig. 3

A model of deregulated NT function following early life allergen exposure. a During postnatal development, ASM and PNECs express NT4, while the innervating nerves express TrkB, thereby establishing a functional connection. b In a neonatal mouse model of allergic inflammation, the levels of NTs are increased. Under this condition, NTs may directly signal in the recruited Trk receptor-expressing immune cells to regulate the survival, cytokine secretion, degranulation, and enhanced phagocytosis. Specifically, NT4 produced by mast cells mediates airway hyperinnervation following early life allergen exposure and indirectly induces airway hyperreactivity and mucus overproduction through nerve-derived neurotransmitters