Brain-derived neurotrophic factor in the airways

Abstract

In addition to their well-known roles in the nervous system, there is increasing recognition that neurotrophins such as brain derived neurotrophic factor (BDNF) as well as their receptors are expressed in peripheral tissues including the lung, and can thus potentially contribute to both normal physiology and pathophysiology of several diseases. The relevance of this family of growth factors lies in emerging clinical data indicating altered neurotrophin levels and function in a range of diseases including neonatal and adult asthma, sinusitis, influenza, and lung cancer. The current review focuses on 1) the importance of BDNF expression and signaling mechanisms in early airway and lung development, critical to both normal neonatal lung function and also its disruption in prematurity and insults such as inflammation and infection; 2) how BDNF, potentially derived from airway nerves modulate neurogenic control of airway tone, a key aspect of airway reflexes as well as dysfunctional responses to allergic inflammation; 3) the emerging idea that local BDNF production by resident airway cells such as epithelium and airway smooth muscle can contribute to normal airway structure and function, and to airway hyperreactivity and remodeling in diseases such as asthma. Furthermore, given its pleiotropic effects in the airway, BDNF may be a novel and appealing therapeutic target.

Keywords: Asthma; Development; Fibrosis; Inflammation; Lung; Neurotrophin.

Figure 1. Production of brain-derived neurotrophic factor (BDNF)

Stimulation by agonists or other molecules leading to elevated Ca²⁺ is a common mechanism for inducing BDNF in cells. Other processes that enhance cAMP, or activate signaling intermediates such as CREB, NFkB, CaM kinases or NFAT may also activate the BDNF gene. BDNF is first produced as a pre-pro-peptide that is then cleaved in the Golgi to produce pro-BDNF that is then packaged into vesicles. Pro-BDNF can also be cleaved intracellularly by furins and vesicular convertases to produce mature BDNF that is also packaged. Vesicular release of pro-BDNF or mature BDNF can then act on neurotrophin receptors to produce effects. Extracellularly, pro-BDNF is cleaved by factors such as matrix metalloproteinases or tissue plasminogens.

Figure 2. Neurotrophins and their receptors

The neurotrophin family consists of four polypeptide proteins that activate two classes of receptors. All of the neurotrophins (NGF, BDNF, NT4 and NT3) bind to the low-affinity p75NTR receptor that lacks a tyrosine kinase domain but can use adaptor proteins. P75NTR is a member of the tumor necrosis factor receptor family. The high-affinity receptors are the tropomyosin related kinases (Trks) that in their full-length (FL) form have an intracellular tyrosine kinase domain via which they function. In addition, ‘truncated” Trks also exist that do not have the tyrosine kinase domain but can act via other mechanisms. NGF preferentially binds to TrkA, while TrkB is the preferred receptor for BDNF and NT4, and TrkC preferentially binds to NT3. In addition, NT3 can bind to the other Trks with lower affinity.

Figure 3. BDNF signaling

As discussed in the main text, BDNF signaling via TrkB vs. p75NTR is complex but elegant, allowing for a diversity of signaling mechanisms and cellular effects that are cell type- and context-dependent. Activation of the full-length TrkB by mature BDNF classically results in activation of PLCγ with downstream effects on [Ca²⁺]_i via the IP3 pathway that can enhance contractility, the ERK pathway and the PI3K/Akt pathway that can both promote cell proliferation and survival. In addition TrkB can work through the NFκB pathway. In contrast to TrkB-FL, the truncated TrkB-T1 can be both inhibitory (red; by dimerizing with TrkB-FL or chelating BDNF) and activating via RhoA and PKC, leading to cytoskeletal remodeling, gene regulation and other effects. The low-affinity p75NTR, when activated by mature BDNF is typically activating to pathways that TrkB-FL works through, but importantly can be inhibitory via the JNK or Akt pathways. This is particularly the case when p75NTR is activated by pro-BDNF and forms a ternary complex with the adaptor protein sortilin.

Figure 4. BDNF and the airway

There is increasing evidence that BDNF can be produced by cells of the airway such as epithelium, airway smooth muscle (ASM), airway nerves, and even fibroblasts. Furthermore, each of these cell types can be a target of BDNF. In the context of airway diseases, BDNF can enhance airway irritability and responsiveness to agonist via the nerves or ASM itself (where [Ca²⁺]_i is increased) or enhance airway remodeling in diseases such as asthma or COPD by increasing cell proliferation, migration, fibrosis and formation of extracellular matrix.