Leukotriene B4 Receptor 1 Expression on Dendritic Cells Is Required for the Development of Th2 Responses and Allergen-Induced Airway Hyperresponsiveness

Abstract

Dendritic cells (DC) are important APCs that control allergen-induced airway responses by interacting directly with T cells. Leukotriene B4 (LTB4), interacting with its high-affinity receptor, LTB4 receptor 1 (BLT1), is known to attract and activate leukocytes during inflammation. We have previously shown that BLT1 expression on Ag-primed T cells is required for the development of airway hyperresponsiveness (AHR; Miyahara et al. 2005. Am. J. Respir. Crit. Care Med. 172: 161–167). However, the role for the LTB4-BLT1 pathway in DC function in allergen-induced airway responses has not been defined. Bone marrow-derived DCs (BMDC) were generated. Naive BALB/c mice received OVA-pulsed BLT1-deficient (BLT1−/−) BMDCs or wild-type BMDCs intratracheally and were then challenged with OVA for 3 days. Airway responses were monitored 48 h after the last allergen challenge. BLT1−/− BMDCs showed normal maturation judged from surface expression of CD markers. Compared with recipients of wild-type BMDCs, mice that received BLT1−/− BMDCs developed significantly lower AHR to inhaled methacholine, lower goblet cell metaplasia, and eosinophilic infiltration in the airways and decreased levels of Th2 type cytokines in the bronchoalveolar lavage fluid. Migration of BLT1−/− BMDCs into peribronchial lymph nodes was significantly impaired compared with BLT1+/+ BMDCs after intratracheal instillation. These data suggest that BLT1 expression on DCs is required for migration of DCs to regional lymph nodes as well as in the development of AHR and airway inflammation.

Plasticity of Invariant NKT Cell Regulation of Allergic Airway Disease Is Dependent on IFN-γ Production

“…aGalCer BMDCs also demonstrated significant increases in levels of IFN-g in PBLNs, where allergen-captured DCs migrate and present Ag to recirculating naive CD4 + and CD8 + cells (7,10,11). In the lungs of recipients of OVA/aGalCer BMDCs, the number of iNKT cells that produced IFN-g was significantly increased compared with the numbers in recipients of OVA BMDCs.…”

“…Because DCs are important APCs in the lung and play a critical role in the induction or the initiation phase of allergic airway inflammation and AHR (7,8), we sought to define whether this ligand for iNKT cells could modify DC function and, in turn, iNKT cell function. To focus on the initiation phase, we showed that transfer of OVA BMDCs intratracheally could initiate the development of AHR and airway inflammation in response to OVA challenge in the absence of prior sensitization with adjuvant (10,11). In this way, allergen-pulsed BMDCs that are exposed to a ligand for iNKT cells may be used to determine the potential role for iNKT cells in the initiation phase, prior to allergen challenge.…”

“…It is unclear whether such effects are restricted to the challenge phase or whether activation of iNKT cells during the sensitization (initiation) phase also regulates development of allergic inflammation and AHR, because they were shown to be a potent producers of Th1-and Th2-type proinflammatory cytokines (29). Intratracheal transfer of Ag-pulsed BMDCs leads to the full development of lung allergic responses on allergen challenge alone, 10 d later (10,11). In this study, we show that transfer of BMDCs treated with aGalCer, a specific ligand of NKT cells, prevented the development of lung allergic responses, and this was dependent on IFN-g production by recipient iNKT cells.…”

“…In the lung, DCs may represent the most important APCs and play an essential role in the induction of allergic airway inflammation and AHR (7,9). Following intratracheal transfer of OVA-pulsed bone marrow-derived dendritic cells (BMDCs), mice develop AHR and eosinophilic airway inflammation after OVA challenge alone (10,11). In such studies, the Ag-pulsed BMDCs replace the active sensitization phase, priming the airways to subsequent allergen challenge.…”

The BLT1 Inhibitory Function of α-1 Antitrypsin Augmentation Therapy Disrupts Leukotriene B4 Neutrophil Signaling

“…LTB 4 exerts a diverse range of effects on the function of these latter immune cells (2) and also the activity of eosinophils, basophils, and lymphocytes (3)(4)(5)(6)(7)(8). Most, if not all, of these immune functions are associated with the BLT1 receptor, with BLT2 generally more associated with cancer progression (9).…”