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Leukotriene B₄ Receptor 1 Expression on Dendritic Cells Is Required for the Development of Th2 Responses and Allergen-Induced Airway Hyperresponsiveness^1,2

Nobuaki Miyahara^3,*, Hiroshi Ohnishi^*, Hiroyuki Matsuda^*, Satoko Miyahara^*, Katsuyuki Takeda^*, Toshiyuki Koya^*, Shigeki Matsubara^*, Masakazu Okamoto^*, Azzeddine Dakhama^*, Bodduluri Haribabu and Erwin W. Gelfand^4,*

^* Division of Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206; and Department of Microbiology and Immunology, James Graham Brown Cancer Center, Louisville, KY 40202

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.

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¹ This work was supported by National Institutes of Health Grants HL-36577 and HL-61005 and by Environmental Protection Agency Grant R825702. N.M. was supported by a grant from the Takeda Science Foundation.

² The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health.

³ Current address: Department of Respiratory Medicine, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan.

⁴ Address correspondence and reprint requests to Dr. Erwin W. Gelfand, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206. E-mail address: gelfande{at}njc.org

⁵ Abbreviations used in this paper: AHR, airway hyperresponsiveness; BAL, bronchoalveolar lavage; BLT1, leukotriene B₄ receptor 1; DC, dendritic cell; BMDC, bone marrow-derived DC; Cdyn, dynamic compliance; LTA₄H, leukotriene A₄ hydrolase; LTB₄, leukotriene B₄; MNC, mononuclear cells; PAS, periodic acid-Schiff; PBLN, peribronchial lymph node; RL, lung resistance; WT, wild type.