Neuroimmune interaction in allergic asthma
The role of the neurotrophin receptors p75NTR, TrkA, TrkB and TrkC
Allergic asthma is a chronic inflammatory disorder with an increased responsiveness of the airways to non-specific stimuli referred to as airway hyperreactivity (AHR). Previous studies indicate that neurotrophin levels in bronchoalveolar lavage fluid (BALF) are increased after allergen provocation in patients suffering from asthma. In addition, a lot of in vivo and in vitro studies provide evidence that these factors, in particular NGF, exert multiple functions on diverse immune cell subpopulations and may be involved in the induction of AHR. The aim of Paper 1 was to investigate whether neurotrophins may affect immune cell function within the airways. We investigated therefore the effects of these factors on survival and activation of eosinophils that were obtained from peripheral blood and BALF after segmental allergen provocation. Our data clearly indicate that both NGF, BDNF, NT-3 and NT-4 increase activation and promote survival, but, interestingly, these effects were restricted to BALF eosinophils. In order to identify the underlying mechanism that caused a different response to neurotrophins in the investigated eosinophil populations, we analyzed neurotrophin receptor expression. We could clearly demonstrate that expression of p75NTR, TrkA, TrkB and TrkC was upregulated in BALF eosinophils compared to blood eosinophils. In conclusion, study 1 was was the first study suggesting that not only NGF, which has been extensively investigated in the past decades, but also BDNF, NT-3 and NT-4 may directly affect immune cell function and may contribute to airway inflammation by direct interaction with the neurotrophin receptors p75NTR, TrkA, TrkB, and TrkC on the surface of BALF eosinophils. Furthermore, this study indicates that neurotrophin receptor expression is regulated in an allergen-dependent manner which has not been described before. In order to analyze which of these neurotrophin receptors may be involved in eosinophilia in vivo, we performed study 2 (shown in Paper 2) in a murine model of allergic asthma. In this model, we could observe a similar allergen-dependent upregulation of neurotrophin receptor mRNA expression in the lung tissue like in human eosinophils. This finding was accompanied by an increase in neurotrophin receptor immunoreactice immune cells located peribronchially and perivascularly. Trk receptors were antagonized by intranasal application of REN1826, a novel soluble pan-Trk receptor decoy, in OVA sensitized and OVA-aerosol challenged mice. Our data indicate that the effects of neurotrophins on eosinophil function in vitro may be probably attributed to p75NTR activation104;145 since the number of eosinophils recruited to the airways was unaltered by treatment with REN1826. However, abrogation of Trk mediated signals significantly reduced Th2 cytokine synthesis pointing out a possible role of Trk receptors in T-lymphocyte regulation. Furthermore, we observed a constitutive Trk receptor expression in nerve fibers surrounding the airways and in airway smooth muscle cells. These cells were implicated in the development of AHR. Therefore, we hypothesized that Trk receptors may play a functional role in the development of AHR. An indeed, antagonization of Trk receptor mediated signals by local treatment with REN1826 reduced the sensitivity of afferent sensory nerves in response to inhaled capsaicin and abrogated reflex bronchospasm after irritation of sensory nerves. In contrast, airway smooth muscle function remained unaltered as indicated by unchanged EF50 values after MCh challenge. Therefore, we suggested that Trk receptors might contribute to AHR by induction of functional changes in sensory nerves. In conclusion, Paper 2 provides new evidence that the neurotrophin/Trk receptor system play a critical role in regulating airway inflammation in vivo and that Trk receptors might contribute to the development of AHR by amplification of sensory nerve reactivity. In summary, the results of both studies indicate that neurotrophins and their receptors may be involved in multiple functional changes of diverse cell types which are key players in allergic asthma. On the basis of our data obtained during this MD/PhD project, we hypothesize that antagonization of neurotrophins or their receptors might be a useful tool in asthma treatment.
Hannover, Medizinische Hochschule, Diss., 2005