Nerve growth factor: The central hub in the development of allergic asthma?
Neurotrophins like nerve growth factor (NGF), originally described as nerve growth factors in neuronal development, have been implicated in many physiological processes in the last years. They are now regarded as important factors involved in the resolution of pathological conditions. NGF has profound effects on inflammation, repair and remodeling of tissues. However, in the lung these beneficial effects can transact into disease promoting actions, e.g., in allergic inflammation or respiratory syncytial virus (RSV) infection. Overproduction of NGF then enhances inflammation, and promotes (neuronal) airway hyperreactivity and neurogenic inflammation. We hypothesize that NGF overexpression in certain vulnerable time windows during infancy could be a major risk factor for the development of asthma symptoms.
[Show abstract] [Hide abstract] ABSTRACT: Nerve growth factor (NGF) and dendritic cells (DCs) have been hypothesized to modulate T cell responses in a mouse model of asthma. However, whether NGF plays a role in regulating the maturation and polarization of lung DCs remains unclear. In the present study, the effect of NGF inhibition on the maturation and phenotype of lung DCs was investigated in a mouse model of asthma. BALB/c mice were sensitized and challenged with ovalbumin (OVA), and subsequently received anti-NGF treatment. At 24 h following the last challenge, airway responsiveness and inflammation were examined. The concentrations of NGF, interferon (IFN)-γ and interleukin (IL)-4 were analyzed. In addition, maturation and CD103 expression in the lung DCs were investigated. Anti-NGF treatment was found to significantly reduce airway hyperreactivity and inflammation in asthmatic mice. In addition, a subdued T helper 2 (Th2) response was observed, characterized by the downregulation of IL-4 and the upregulation of IFN-γ. Furthermore, the expression of the DC surface molecules, CD80, CD86 and major histocompatibility complex class II, as well as the proportion of lung CD103(+) DCs, decreased in the OVA-sensitized and challenged mice. The proportion of lung CD103(+) DCs also exhibited a positive correlation with the levels of plasma NGF in the mice. These results may provide an explanation for the role of NGF in amplifying the Th2 response in allergic diseases. Therefore, NGF may promote the maturation and polarization towards a Th2-stimulating phenotype of activated DCs, contributing to an amplification of the Th2 response in asthma.0Comments 2Citations
- "Asthma is a chronic inflammatory airway disease characterized by recurrent episodes of wheezing, breathlessness, chest tightness and coughing driven by an aberrant T helper 2 (Th2) immune response to environmental allergens (2). In addition to its classical nervous system domain, nerve growth factor (NGF) is regarded as an important factor involved in the pathogenesis of allergic diseases, including asthma (3). Studies in ovalbumin sensitized and challenged asthmatic mice with anti-NGF antibody (4) or small interfering RNA (5) have shown that blocking NGF can improve airway inflammation. "
[Show abstract] [Hide abstract] ABSTRACT: Nerve growth factor (NGF) is overexpressed in patients with inflammatory lung diseases, including virus infections. Airway surface liquid (ASL), which is regulated by epithelial cell ion transport, is essential for normal lung function. No information is available regarding the effect of NGF on ion transport of airway epithelium. To investigate whether NGF can affect ion transport, human primary air-interface cultured epithelial cells were placed in Ussing chambers to obtain transepithelial voltage (−7.1 ± 3.4 mV), short-circuit current (Isc, 5.9 ± 1.0 μA), and transepithelial resistance (750 Ω·cm2), and to measure responses to ion transport inhibitors. Amiloride (apical, 3.5 × 10−5 mol/L) decreased Isc by 55.3%. Apically applied NGF (1 ng/mL) reduced Isc by 5.3% in 5 min; basolaterally applied NGF had no effect. The response to amiloride was reduced (41.6%) in the presence of NGF. K-252a (10 nmol/L, apical) did not itself affect Na+ transport, but it attenuated the NGF-induced reduction in Na+ transport, indicating the participation of the trkA receptor in the NGF-induced reduction in Na+ transport. PD-98059 (30 μmol/L, apical and basolateral) did not itself affect Na+ transport, but attenuated the NGF-induced reduction in Na+ transport, indicating that trkA activated the Erk 1/2 signaling cascade. NGF stimulated phosphorylation of Erk 1/2 and the β-subunit of ENaC. K-252a and PD-98059 inhibited these responses. NGF had no effect on Isc in the presence of apical nystatin (50 μmol/L). These results indicate that NGF inhibits Na+ transport through a trkA-Erk 1/2-activated signaling pathway linked to ENaC phosphorylation.0Comments 1Citation
- "Although NGF was discovered in the context of nerve growth and function, it has been shown to be produced by both structural and nonstructural cells in the lung (Hoyle 2003; Frossard et al. 2004). NGF is involved in the development of several airway diseases, such as asthma, and neurogenic inflammation (Braun et al. 1998; Nassenstein et al. 2006). Elevated levels of NGF have been shown to cause airway hyperreactivity, enhance the airway inflammatory response in ovalbumin-sensitized mice, and cause airway remodeling (Braun et al. 1998; Freund and Frossard 2004). "
[Show abstract] [Hide abstract] ABSTRACT: Nerve growth factor (NGF) is a neurotrophin crucial for the development and survival of neurons. It also acts on cells of the immune system which express the NGF receptors TrkA and p75(NTR) and can be produced by them. However, mouse NK cells have not yet been studied in this context. We used cell culture, flow cytometry, confocal microscopy and ELISA assays to investigate the expression of NGF receptors by NK cells and their secretion of NGF. We show that resting NK cells express TrkA and that the expression is different on NK cell subpopulations defined by the relative presence of CD27 and CD11b. Expression of TrkA is dramatically increased in IL-2-activated NK cells. The p75(NTR) is expressed only on a very low percentage of NK cells. Functionally, NGF moderately inhibits NK cell degranulation, but does not influence proliferation or cytokine production. NK cells do not produce NGF. We demonstrate for the first time that mouse NK cells express the NGF receptor TrkA and that this expression is dynamically regulated.0Comments 8Citations
- "This control consisted in bronchoalveolar lavage fluid (BALF) of mice sensitized to ovalbumin in the context of another project. It is known that BALF of mice with an allergic inflammation of the airways contains high levels of NGF . This showed that the ELISA assay efficiently detected NGF and that the failure to demonstrate NGF production by NK cells was not due to a technical problem. "