Background Activated TH 2 cells and eosinophils are hallmarks of the allergic inflammation seen in patients with allergic rhinitis (AR). However, which cells activate and attract T cells and ...eosinophils to the inflammatory lesion has not been determined. Objective We wanted to assess the role of mucosal mononuclear phagocytes, consisting of monocytes, macrophages, and dendritic cells, in the local allergic inflammatory reaction. Methods Patients with AR and nonatopic control subjects were challenged with pollen extract, and nasal symptoms were recorded. Mucosal biopsy specimens obtained at different time points before and after challenge were used for immunostaining in situ and flow cytometric cell sorting. Sorted mononuclear phagocytes were subjected to RNA extraction and gene expression profiling. Results In an in vivo model of AR, we found that CD14+ monocytes were recruited to the nasal mucosa within hours after local allergen challenge, whereas conventional dendritic cells accumulated after several days of continued provocation. Transcriptomic profiling of mucosal mononuclear phagocytes sorted after 1 week of continued allergen challenge showed an activated phenotype at least partially driven by IL-4 signaling, IL-13 signaling, or both. Importantly, gene expression of several TH 2-related chemokines was significantly upregulated by the mononuclear phagocyte population concomitant with an increased recruitment of CD4+ T cells and eosinophils. Conclusion Our findings suggest that the mononuclear phagocyte population is directly involved in the production of proinflammatory chemokines that attract other immune cells. Rapid recruitment of CD14+ monocytes to the challenged site indicates that these proinflammatory mononuclear phagocytes have a central role in orchestrating local allergic inflammation.
Background Thymic stromal lymphopoietin (TSLP) controls allergic TH 2 inflammatory responses through induction of distinct activation programs in dendritic cells (DCs). However, knowledge about TSLP ...receptor expression and functional consequences of receptor activation by DCs residing in the human respiratory tract is limited. Objective We wanted to identify TSLP-responding DC populations in the human upper airway mucosa and assess the TSLP-mediated effects on such DCs in allergic airway responses. Results We found that the TSLP receptor was constitutively and preferentially expressed by myeloid CD1c+ DCs in the human airway mucosa and that the density of this DC subset in nasal mucosa increased significantly after in vivo allergen challenge of patients with allergic rhinitis. In vitro , TSLP strongly enhanced the capacity of CD1c+ DCs to activate allergen-specific memory CD4+ T cells. Moreover, TSLP rapidly induced CCR7 expression on CD1c+ DCs. However, TH 2 cytokines attenuated TSLP-mediated CCR7 induction, thus inhibiting the TSLP-induced DC migration potential to the draining lymph nodes. Conclusion Our results suggest that TSLP-mediated activation of human nasal mucosal CD1c+ DCs triggers CCR7-dependent migration to the draining lymph nodes and enhances their capacity to initiate TH 2 responses. However, the observation that TH 2 cytokines abrogate the induction of CCR7 implies that during a TH 2-mediated inflammatory reaction, TLSP-activated CD1c+ DCs are retained in the inflamed tissue to further exacerbate local inflammation by activating local antigen-specific memory TH 2 cells.
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