Neuroimmune crosstalk in asthma: dual role of the neurotrophin receptor p75NTR.
BACKGROUND
Neurotrophins have been implicated in the pathogenesis of asthma because of their ability to induce airway inflammation and to promote hyperreactivity of sensory neurons, which reflects an important mechanism in the pathogenesis of airway hyperreactivity. Neurotrophins use a dual-receptor system consisting of Trk-receptor tyrosine kinases and the structurally unrelated p75NTR. Previous studies revealed an important role of p75NTR in the pathogenesis of allergic asthma.


OBJECTIVE
The aim of the study was to investigate the precise mechanisms of neurotrophins in neuroimmune interaction, which can lead to both airway inflammation and sensory nerve hyperreactivity in vivo.


METHODS
Mice selectively expressing p75NTR in immune cells or nerves, respectively, were generated. After sensitization and allergen provocation, hyperreactivity of sensory nerves was tested in response to capsaicin. Airway inflammation was analyzed on the basis of differential cell counts and cytokine levels in bronchoalveolar lavage fluids.


RESULTS
Allergic mice selectively expressing p75NTR in immune cells showed normal inflammation but no sensory nerve hyperreactivity, whereas mice selectively expressing p75NTR in nerve cells had a diminished inflammation and a distinct sensory nerve hyperreactivity.


CONCLUSIONS
Our data indicate that p75NTR plays a dual role by promoting hyperreactivity of sensory nerves and airway inflammation. Additionally, our study provides experimental evidence that development of sensory nerve hyperreactivity depends on an established airway inflammation in asthma. In contrast, development of airway inflammation seems to be independent from sensory nerve hyperreactivity.


CONCLUSIONS
Because of its dual function, antagonization of p75NTR-mediated signals might be a novel approach in asthma therapy.
Nassenstein
Christina
C
Department of Immunology, Allergology and Immunotoxicology, Fraunhofer Institute of Toxicology and Experimental Medicine, Hannover, Germany.
Kammertoens
Thomas
T
Veres
Tibor Zoltan
TZ
Uckert
Wolfgang
W
Spies
Emma
E
Fuchs
Barbara
B
Krug
Norbert
N
Braun
Armin
A
D000344:Afferent Pathways / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D007249:Inflammation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009414:Nerve Growth Factors / Q000032:analysis / Q000378:metabolism*; D009475:Neurons, Afferent / Q000276:immunology*; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000502:physiology*
D009414:Nerve Growth Factors; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse