title: Cysteinyl leukotriene 2 receptor on dendritic cells negatively regulates ligand-dependent allergic pulmonary inflammation.
abstract: 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 (LTC(4)S), CysLT(1)R, or both CysLT(2)R/LTC(4)S, suggesting that CysLT(2)R negatively regulates LTC(4)S- and CysLT(1)R-dependent DC-mediated sensitization. CysLT(2)R-deficient BMDCs had increased CysLT(1)R-dependent LTD(4)-induced ERK phosphorylation, whereas N-methyl LTC(4) 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 LTD(4) and N-methyl LTC(4), 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/LTC(4)S-deficient BMDCs. Importantly, treatment with N-methyl LTC(4) 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 LTC(4)S-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.
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nora A
authors.initials: NA
authors.lastname: Barrett
authors.forename: James M
authors.initials: JM
authors.lastname: Fernandez
authors.forename: Akiko
authors.initials: A
authors.lastname: Maekawa
authors.forename: Wei
authors.initials: W
authors.lastname: Xing
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Parsons
authors.forename: K Frank
authors.initials: KF
authors.lastname: Austen
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Kanaoka
mesh_terms: D000818:Animals; D039741:Antigens, Dermatophagoides / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D040001:Dermatophagoides farinae / Q000276:immunology*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D004802:Eosinophilia / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018077:Receptors, Leukotriene / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D012130:Respiratory Hypersensitivity / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000276:immunology
chemical_list: D039741:Antigens, Dermatophagoides; D018836:Inflammation Mediators; D008024:Ligands; D018077:Receptors, Leukotriene; C412375:cysteinyl leukotriene receptor 2; C083169:leukotriene D4 receptor