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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Eu, Jerry Pc
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Brigham and Women's Hospital
United States
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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