| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Department of Medicine, Harvard Medical School, and Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Boston, MA 02115
House dust mites are a significant source of airborne allergen worldwide, but there is little understanding of how they so potently generate allergic inflammation. We found that extracts from the house dust mites Dermatophagoides farinae (Df) and Dermatophagoides pteronyssinus and from the mold Aspergillus fumigatus stimulated a rapid and robust production of cysteinyl leukotrienes (cys-LTs), proinflammatory lipid mediators, from mouse bone marrow-derived dendritic cells (BMDCs). Con A affinity chromatography of the Df extract revealed that the relevant ligand is a glycan(s), suggesting stimulation via a dendritic cell (DC) lectin receptor. Cys-LT production in BMDCs from wild-type mice was inhibited by spleen tyrosine kinase (Syk) inhibitors and was abolished in BMDCs from FcR
–/– mice, implicating either Dectin-2 or DC immunoactivating receptor. Transfection of each receptor in bone marrow-derived mast cells revealed that only Dectin-2 mediates cys-LT production by Df, Dermatophagoides pteronyssinus, and Aspergillus fumigatus. Lentiviral knockdown of Dectin-2 in BMDCs attenuated Df extract-elicited cys-LT generation, thereby identifying Dectin-2 as the receptor. Lung CD11c+ cells, but not peritoneal or alveolar macrophages, also generated cys-LTs in response to Df. These findings place Dectin-2 among the C-type lectin receptors that activate arachidonic acid metabolism and identify the Dectin-2/FcR/Syk/cys-LT axis as a novel mechanism by which three potent indoor allergens may activate innate immune cells to promote allergic inflammation.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants AI-07306, AI-31599, AI-52353, HL-36110, and HL-82695. N.A.B. is supported by an American Academy of Allergy, Asthma, and Immunology/Altana grant for advanced fellows-in-training and the Joycelyn C. Austen Fund for the Career Development of Women Physician Scientists.
2 Address correspondence and reprint requests to Dr. Yoshihide Kanaoka, Brigham and Women’s Hospital, Smith Building, Room 626C, One Jimmy Fund Way, Boston, MA 02115. E-mail address: ykanaoka{at}rics.bwh.harvard.edu
3 Abbreviations used in this paper: PRR, pattern recognition receptor; DC, dendritic cell; CLR, C-type lectin receptor; Nod, nucleotide-binding oligomerization domain; PGN, peptidoglycan; cys-LT, cysteinyl leukotriene; LT, leukotriene; 5-LO, 5-lipoxygenase; WT, wild type; Df, Dermatophagoides farinae; BMDC, bone marrow-derived DC; Dp, Dermatophagoides pteronyssinus; Af, Aspergillus fumigatus; Pa, Periplaneta americana; Bg, Blattella germanica; MHC class II, MHCII+; DCAR, DC immunoactivating receptor; BMMC, bone marrow-derived mast cell; shRNA, short hairpin RNA; DC-SIGN, DC-specific ICAM-3 grabbing nonintegrin; Syk, spleen tyrosine kinase; LTC4S, LTC4 synthase.
Related articles in The JI:
This article has been cited by other articles:
|
|
 |
|
  M. J. Robinson, F. Osorio, M. Rosas, R. P. Freitas, E. Schweighoffer, O. Gross, J. S. Verbeek, J. Ruland, V. Tybulewicz, G. D. Brown, et al. Dectin-2 is a Syk-coupled pattern recognition receptor crucial for Th17 responses to fungal infection J. Exp. Med., August 31, 2009; 206(9): 2037 - 2051. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
