Brigham and Women's Hospital
Smith Building, Room 626c
1 Jimmy Fund Way
Boston, MA 2115
Eicosanoids are lipid mediators derived from arachidonic acid that have been implicated in diverse inflammatory and immune responses. The cysteinyl leukotrienes (cys-LTs), leukotriene (LT) C4, LTD4, and LTE4, are a group of bioactive eicosanoids that are produced by hematopoietic cells, such as mast cells, macrophages, and dendritic cells. They constrict bronchial smooth muscle, increase vascular permeability, and promote fibrosis. LTC4 synthase, an integral membrane protein, is the critical enzyme for the cys-LT biosynthesis. There are two classical G protein-coupled receptors for the cys-LTs, termed CysLT1R and CysLT2R. We are focused on elucidating the role of cys-LTs in several models of innate and adaptive immunity and inflammation with mice null for LTC4 synthase and on clarifying the particular receptor functions in these models with mice null for CysLT1R or CysLT2R. We have recently found that there is a novel cys-LT receptor preferential for LTE4 in mice lacking both CysLT1R and CysLT2R. We have also found that an orphan G protein-coupled receptor GPR17 is a negative regulator of the CysLT1R-mediated vascular permeability in vivo. Ongoing projects include (1) the molecular identification and characterization of the LTE4 receptor and (2) the role of GPR17 in allergen-induced pulmonary inflammation.
Dectin-2 is a C-type lectin receptor that associates with the Fc receptor gamma chain to activate the signal through Syk. We have demonstrated that Dectin-2 on dendritic cells can bind to extracts from house dust mite in a mannose-dependent manner, resulting in production of cys-LTs. We are investigating the role of Dectin-2 in allergen-induced pulmonary inflammation.
Maekawa A, Kanaoka Y, Xing W, Austen KF. Functional recognition of a distinct receptor preferential for leukotriene E4 in mice lacking the cysteinyl leukotriene 1 and 2 receptors. Proc Natl Acad Sci USA 2008;105:16695-700.
Barrett NA, Maekawa A, Rahman M, Austen KF, Kanaoka Y. Dectin-2 recognition of house dust mite triggers cysteinyl leukotriene generation by dendritic cells. J Immunol 2009;182:1119-28.
Maekawa A, Balestrieri B, Austen KF, Kanaoka Y. GPR17 is a negative regulator of the cysteinyl leukotriene 1 receptor response to leukotriene D4. Proc Natl Acad Sci USA 2009;106:11685-90.
Maekawa A, Xing W, Austen KF, Kanaoka Y. GPR17 regulates immune pulmonary inflammation induced by house dust mites. J Immunol 2010;185:1846-54.
Barrett NA, Rahman OM, Fernandez JM, Parsons MW, Xing W, Austen KF, Kanaoka Y. Dectin-2 mediates Th2 immunity through the generation of cysteinyl leukotrienes. J Exp Med 2011;208:593-604.
Last Update: 1/6/2014