This application to support a new early stage investigator focuses on the role of Dectin-2 in the pathophysiology of allergen-induced pulmonary inflammation. We have previously discovered that the dendritic cell (DC) C-type lectin receptor Dectin-2 is activated by glycans found in common, clinically relevant, allergens such as the house dust mite (HDM) species Dermatophagoides farinae (Df) and Dermatophagoides pteronyssinus (Dp) and the mold Aspergillus fumigatus (Af). Activation of Dectin-2 by Df, Dp, or Af triggers production of pro-inflammatory cytokines (IL-23, IL-1 beta, IL-6, and TNF-?) and cysteinyl leukotrienes (cys- LTs). Cys-LTs produced by such activation condition DCs in an autocrine fashion to promote Th2 immune responses, via the type 1 receptor for cysteinyl leukotrienes (cys-LTs), CysLT1R. CysLT1R signaling and Th2 priming on DCs are negatively regulated by the type 2 receptor for cys-LTs, CysLT2R. These data suggest that Th2 immunity to allergens can be finely regulated by signaling from cys-LTs. The current proposal will use mouse strains with genetic mutations in classical and novel CysLTRs to understand how they influence DC activation and Th2 priming to native allergens (Aim 1). Human monocyte-derived DCs will also be assessed by using siRNA-mediated knockdown of CysLTRs. We have identified that Dectin-2 has a critical role in triggering allergic inflammation during the challenge phase and Aim 2 of the current proposal will use in vivo models of HDM sensitization and challenge to understand the role of Dectin-2 and DCs in the elicitation phase. Greater than 50% of asthma is attributable to allergy and HDM is the most common allergen worldwide. Therefore, understanding how Dectin-2 mediates sensitization and propagation of HDM-triggered immunopathology offers a MAJOR potential therapeutic benefit.

Public Health Relevance

Asthma is a common and serious disease. Greater than 50% of asthma is attributable to allergy and house dust mite is the most common allergen worldwide. We have identified that the immune receptor Dectin-2 is activated by dust mite to initiate and perpetuate allergic pulmonary inflammation. Therefore, understanding how Dectin-2 mediates the response to dust mite can identify novel targets for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL120952-01
Application #
8612049
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Eu, Jerry Pc
Project Start
2014-01-01
Project End
2018-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
1
Fiscal Year
2014
Total Cost
$364,994
Indirect Cost
$139,994
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Tjota, Melissa Y; Hrusch, Cara L; Blaine, Kelly M et al. (2014) Signaling through FcR?-associated receptors on dendritic cells drives IL-33-dependent TH2-type responses. J Allergy Clin Immunol 134:706-713.e8
Parsons, Matthew W; Li, Li; Wallace, Aaron M et al. (2014) Dectin-2 regulates the effector phase of house dust mite-elicited pulmonary inflammation independently from its role in sensitization. J Immunol 192:1361-71