Dendritic cells play a pivotal role as antigen sampling and presenting cells in the initiation and development of allergic response such as allergic airway inflammation
[3, 4, 8]. Previous studies have revealed that DCs were found to be localised in the neighbourhood of peripheral CGRP-positive nerve fibres in the airways
. The role of this DC-nerve interaction in allergic airway inflammation, however, has not been clear yet.
CGRP has been discussed to have the capacity to modulate DCs during the allergic airway inflammation. CGRP is known to be produced by the cell bodies located in JNC, anterogradely transported and released by the peripheral nerve fibres innervating the airways
[12–14]. In this respect, the present study aimed to investigate the localisation, distribution and proliferation of DCs in JNC by using HDM mouse model for allergic airway inflammation.
After continuous intranasal administration with HDM extract, a chronic airway inflammation was induced as previously reported
. In accordance to other studies, inhalation of HDM extract led to a significant increase of the recruitment of eosinophils as well as a substantial number of neutrophils, macrophages and lymphocytes
[27, 28]. With the characteristic of mixed eosinophilic and neutrophilic inflammation, the HDM mouse model becomes an interesting animal model that may closely reflect the situation of severe bronchial asthma in human
Interestingly, for the first time, cells expressing MHC II molecules were identified in JNC of mice under physiological conditions. The immunofluorescence analysis revealed that these cells belong to the immune cell population rather than to the nervous system as they were non-reactive for the pan-neuronal marker PGP 9.5. Additionally, these immune cells exhibited DC phenotypes as they displayed high immunoreactivity for MHC II and CD103 while negative for CD11b- and F4/80-immunoreactivity. Most (about 98%) of MHC II-IR cells were immunoreactive for CD11c indicating these cells are DCs. MHC II-IR cells have also been found to be totally colocalised with Iba1, which has been reported to be expressed in DCs in the brain and other organs such as intestine and skin
[5, 30, 31]. A very small population with MHC II-IR did not express CD11c (<2%). These cell types are still unknown and remain to be investigated in future study.
The localisation of DCs within the sensory ganglia was found to be widely distributed on the whole ganglia and between SGCs and/or neurons. Recently, other neuronal cells, such as SGCs in human trigeminal ganglion, have also been shown to express MHC II
. However, the present findings revealed that SGCs in mouse JNC to be negative for MHC II. The contrary findings of the SGC population may be caused by the ganglionic- and species-specific differences between mouse and human
[29, 32]. The exact role of SGCs in JNC under physiological and allergic situations remains to be investigated in future experiments.
For the discrimination of DC migration into the ganglia as a targeted infiltration and systemic infiltration, further studies have been carried out in trigeminal ganglia. In contrast to the JNC, where the numbers of DCs were significantly increased during allergic airway inflammation, the numbers of MHC II-IR cells in trigeminal ganglia, however, were not changed. These contrary findings may be caused by the ganglionic- or organ-specific differences between JNC and trigeminal ganglia. Anatomically, trigeminal ganglia are located inside the cranium, whereas JNC are found to be under the skullbase. Additionally, the two ganglia have different embryonic development.
The findings of the increase of DCs in the JNC lead to further questions of their origin. The results of the proliferation study suggest that DCs may move from the systemic blood circulation into JNC by passing through the ganglion-blood barrier. In contrast to the brain–blood barrier, the ganglion-blood barrier is known to be only discontinuously formed
. Alternatively, DCs may reach the JNC along the vagus from the peripheral airways by retrograde migration when their numbers in the airways and the blood system were to be enhanced during allergic airway inflammation
[34, 35]. The presence of DCs in JNC also may play a substantial role in the immune response to protect the neurons against viral and bacterial infection, virus replication and bacterial spread without any neuronal destruction
[36–39]. In this respect, other immune cells like T cells and macrophages were recently found inside the HSV-1 latently infected trigeminal ganglia
. However, the origin and function of the DCs in JNC under normal and allergic airway conditions remains to be answered in future studies.
With respect to the neuroimmune interaction, maturation, migration and function of DCs during allergic airway inflammation have been reported to be modulated by neuropeptides like the calcitonin gene-related peptide (CGRP), tachykinins and vasoactive intestinal peptide (VIP) released from airway nerves fibers
[9, 10, 13, 14]. In view of modulatory effects of CGRP on DCs, sensory neurons in JNC were investigated for CGRP-expression. The significant increase of CGRP-IR-neurons and the elevated numbers of DCs in allergic airway response suggest that there may be a functional relationship between DCs and CGRP-IR-neurons.
The increased of CGRP-IR-neurons in HDM-treated mice may have an influence on the migration, proliferation or function of DCs in JNC. With respect to the effect of CGRP in allergic airway inflammation, a proinflammatory or antiinflammatory role of CGRP in allergic airway inflammation is therefore still controversially discussed
[9, 10, 12, 40]. The intragangionic release of CGRP within JNC has not been demonstrated so far in vivo. Previous study on rat has reported about the release of CGRP from isolated JNC after stimulation with different substances such as capsaicin, nitric oxide donor sodium nitroprusside
. Our findings showed an increase of CGRP-positive neurons in JNC, but a release of CGRP from the neuron into the ganglia could not be demonstrated in the present study. Based on this observation, we suggest that CGRP may be paracrinely released from the neurons or anterogradely transported to the peripheral nerve endings and liberated into the airways. The exact role of CGRP in sensory neurons concerning the modulation of DC-function during allergic airway response remains to be elucidated in future studies.