Untersuchung der Bedeutung des auf plasmazytoiden dendritischen Zellen exprimierten CD271 Rezeptors für die Pathogenese des allergischen Asthma
Zusammenfassung der Projektergebnisse
Plasmacytoid dendritic cells (pDCs) regulate innate and adaptive immune responses. We for the first time demonstrate the expression and immune-regulatory function of the low affinity neurotrophin receptor p75NTR on murine and human pDCs. Binding of neurotrophin nerve growth factor (NGF) to p75NTR results in attenuated interferon α secretion in response to Toll-like receptor-9 activation by CpG A, but increased the secretion of interleukin (IL-)6 in response to CpG B. In the presence of NGF, murine pDCs stimulated the proliferation of CD4+ T cells and induced the secretion of tumor necrosis factor-α and IL-6 in a p75NTR-dependent manner. CD8+ T cells exhibited opposite characteristics. Effects were mediated by differential phosphorylation of the transcription regulatory factors IRF3, IRF7, IKKα/β and c-Jun. Using a murine model of ovalbumin-induced asthma, we showed that p75NTR expression by pDCs was essential for mediating allergic inflammation characterized by increased IL-4, IL-5, and IL-13 secretion; eosinophilia; lung tissue inflammation; and Goblet cell hyperplasia. Stimulation of pDCs with NGF exacerbated allergic symptoms. Our central finding that functional expression of p75NTR by pDCs is a prerequisite of T H2- mediated allergic sensitization and asthma induction in mice, provides a promising target in the search for future therapeutic interventions in allergic diseases, inflammatory disorders, and autoimmune diseases. In very preliminary experiments following the described project, we see also the potential of p75NTR expressing pDCs to regulate type I diabetes and influence graft versus host disease demonstrating the general impact of our findings for future clinical applications. Based on the described work, we have submitted a European patent to use our knowledge for perspective scientific and applications.
