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: Nora A Barrett, James M Fernandez, Akiko Maekawa, Wei Xing, Li Li, Matthew W Parsons, K Frank Austen, Yoshihide Kanaoka
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 189 Issue 9 Pg. 4556-65 (Nov 01 2012) ISSN: 1550-6606 [Electronic] United States
• PMID: 23002438 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Dermatophagoides
• Inflammation Mediators
• Ligands
• Receptors, Leukotriene
• cysteinyl leukotriene receptor 2
• leukotriene D4 receptor

Topics

• Animals
• Antigens, Dermatophagoides (metabolism)
• Dendritic Cells (immunology, metabolism, pathology)
• Dermatophagoides farinae (immunology)
• Down-Regulation (genetics, immunology)
• Eosinophilia (immunology, metabolism, pathology)
• Inflammation Mediators (metabolism, physiology)
• Ligands
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Receptors, Leukotriene (deficiency, metabolism, physiology)
• Respiratory Hypersensitivity (immunology, metabolism, pathology)
• Signal Transduction (immunology)