Cysteinyl Leukotriene 2 Receptor on Dendritic Cells Negatively Regulates Ligand-Dependent Allergic Pulmonary Inflammation

Cysteinyl leukotrienes (cys-LTs) can mediate Th2 immunity to the house dust mite, Dermatophagoides farinae, via the type 1 receptor CysLT(1)R on dendritic cells (DCs). However, the role of the homologous type 2 receptor CysLT(2)R in Th2 immunity is unknown. D. farinae sensitization and challenge of CysLT(2)R-deficient mice showed a marked augmentation of eosinophilic pulmonary inflammation, serum IgE, and Th2 cytokines. Wild-type (WT) mice sensitized by adoptive transfer of D. farinae-pulsed CysLT(2)R-deficient bone marrow-derived DCs (BMDCs) also had a marked increase in D. farinae-elicited eosinophilic lung inflammation and Th2 cytokines in restimulated hilar nodes. This response was absent in mice sensitized with D. farinae-pulsed BMDCs lacking leukotriene C-4 synthase (LTC4S), CysLT(1)R, or both CysLT(2)R/LTC4S, suggesting that CysLT(2)R negatively regulates LTC4S- and CysLT(1)R-dependent DC-mediated sensitization. CysLT(2)R-deficient BMDCs had increased CysLT(1)R-dependent LTD4-induced ERK phosphorylation, whereas N-methyl LTC4 activation of CysLT(2)R on WT BMDCs reduced such signaling. Activation of endogenously expressed CysLT(1)R and CysLT(2)R occurred over an equimolar range of LTD4 and N-methyl LTC4, respectively. Although the baseline expression of cell surface CysLT(1)R was not increased on CysLT(2)R-deficient BMDCs, it was upregulated at 24 h by a pulse of D. farinae, compared with WT or CysLT(2)R/LTC4S-deficient BMDCs. Importantly, treatment with N-methyl LTC4 reduced D. farinae-induced CysLT(1)R expression on WT BMDCs. Thus, CysLT(2)R negatively regulates the development of cys-LT-dependent Th2 pulmonary inflammation by inhibiting both CysLT(1)R signaling and D. farinae-induced LTC4S-dependent cell surface expression of CysLT(1)R on DCs. Furthermore, these studies highlight how the biologic activity of cys-LTs can be tightly regulated by competition between these endogenously expressed receptors. The Journal of Immunology, 2012, 189: 4556-4565.