Dectin-2 sensing of house dust mite is critical for the initiation of airway inflammation

Clarke, D. S.; Davis, Neil; Campion, Cécilia; Foster, Martyn; Heasman, Stephanie; Lewis, Arthur; Anderson, Ian K.; Corkill, Dominic J.; Sleeman, Matthew A.; May, Richard; Robinson, Matthew

doi:10.1038/mi.2013.74

Cited by 60 publications

(56 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Dectin-2 knockdown in murine bone marrow-derived dendritic cells (BMDCs) attenuates their capacity to sensitize wild-type (WT) recipients for the generation of Th2 pulmonary inflammation and lymph node expansion after Df challenge (6). Moreover, administration of the Dectin-2 blocking antibody solely during sensitization, similarly attenuates eosinophilic pulmonary inflammation and airways hyperresponsiveness induced by HDM (21). Although Dectin-2 has an established role in sensitization, the influence of this receptor in regulating systemic immunity and tissue inflammation in effector phase responses is unknown.…”

Section: Introductionmentioning

confidence: 99%

Dectin-2 Regulates the Effector Phase of House Dust Mite–Elicited Pulmonary Inflammation Independently from Its Role in Sensitization

Parsons

Wallace

et al. 2014

The Journal of Immunology

View full text Add to dashboard Cite

The myeloid C-type lectin receptor Dectin-2 directs the generation of Th2 and Th17 immune responses to the house dust mite Dermatophagoides farinae (Df) through the generation of cysteinyl leukotrienes (cys-LTs) and pro-inflammatory cytokines, respectively, but a role for Dectin-2 in effector phase responses has not been described. Here, we demonstrate that administration of the Dectin-2 mAb solely at the time of Df challenge abrogated eosinophilic and neutrophilic inflammation in the bronchoalveolar lavage (BAL) fluid and Th1, Th2, and Th17 inflammation in the lung of previously sensitized mice. Furthermore, Dectin-2 null mice (Clec4n−/−) sensitized with the adoptive transfer of Df-pulsed wild-type (WT) bone marrow-derived DCs (BMDCs) also had less Df-elicited pulmonary inflammation, supporting an effector function for Dectin-2. The protection from pulmonary inflammation seen with the Dectin-2 mAb or in Clec4n−/− mice was associated with little or no reduction in lung-draining lymph node cells or their cytokine production, and with no reduction in serum IgE. WT and Clec4n−/− mice recipients, sensitized with Df-pulsed WT BMDCs, had comparable levels of Df-elicited IL-6, IL-23, TNF-α, and cys-LTs in the lung. By contrast, Df-elicited CCL4 and CCL8 production from pulmonary CD11c+CD11b+Ly6C+ and CD11c+CD11b+Ly6C−CD64+ monocyte-derived DCs was reduced in Clec4n−/− recipients. Addition of CCL8 at the time of Df challenge abrogated the protection from eosinophilic, neutrophilic, and Th2 pulmonary inflammation seen in Clec4n−/− recipients. Taken together, these results reveal that Dectin-2 regulates monocyte-derived DC function in the pulmonary microenvironment at Df challenge to promote the local inflammatory response.

show abstract

Section: Introductionmentioning

confidence: 99%

Dectin-2 Regulates the Effector Phase of House Dust Mite–Elicited Pulmonary Inflammation Independently from Its Role in Sensitization

Parsons

Wallace

et al. 2014

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…We and others have identified a role for Dectin-2 in the generation of both Th2 and Th17-dependent allergic pulmonary inflammation to HDM (14, 15, 19, 50). Here we demonstrate that PI3Kδ signaling in DCs is required for this function, as the adoptive transfer of PI3Kδ-inhibited Df -DC had a reduced capacity to generate Th2 and Th17-dependent allergic pulmonary inflammation.…”

Section: Discussionmentioning

confidence: 84%

Phosphoinositide 3-Kinase δ Regulates Dectin-2 Signaling and the Generation of Th2 and Th17 Immunity

Lee

Yoshimoto

Saijo

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

The C-type lectin receptor (CLR) Dectin-2 can trigger the leukotriene C4 synthase (LTC4S)-dependent generation of cysteinyl leukotrienes (cys-LTs) and the CARD9- and NF-κB-dependent generation of cytokines, such as IL-23, IL-6, and TNF-α, to promote Th2 and Th17 immunity, respectively. Dectin-2 activation also elicits the type 2 cytokine IL-33, but the mechanism by which Dectin-2 induces these diverse innate mediators is poorly understood. Here we identify a common upstream requirement for phosphoinositide 3-kinase delta (PI3Kδ) activity for the generation of each Dectin-2-dependent mediator elicited by the house dust mite species, Dermatophagoides farinae (Df), using both pharmacologic inhibition and siRNA knockdown of PI3Kδ in bone marrow-derived dendritic cells (BMDCs). PI3Kδ activity depends on Spleen tyrosine kinase (Syk) and regulates the activity of protein kinase Cδ, indicating that PI3Kδ is a proximal Syk-dependent signaling intermediate. Inhibition of PI3Kδ also reduces cys-LTs and cytokines elicited by Dectin-2 cross-linking, confirming the importance of this molecule in Dectin-2 signaling. Using an adoptive transfer model, we demonstrate that inhibition of PI3Kδ profoundly reduces the capacity of BMDCs to sensitize recipient mice for Th2 and Th17 pulmonary inflammation in response to Df. Furthermore, administration of a PI3Kδ inhibitor during the sensitization of WT mice prevents the generation of Df-induced pulmonary inflammation. These results demonstrate that PI3Kδ regulates Dectin-2 signaling and its DC function.

show abstract

“…Since a majority of atopic asthmatics show hypersensitivity to house dust mite (HDM) (18), we modeled atopic asthma using a murine model driven by exposure to HDM modified from Clarke et al (19). Briefly, wild-type (WT) and αT-cat knockout (KO) mice were exposed to 50μg HDM extract intranasally over 3 weeks (Fig.…”

Section: Resultsmentioning

confidence: 99%

The cardiomyocyte protein αT-catenin contributes to asthma through regulating pulmonary vein inflammation

Folmsbee

Budinger

Bryce

et al. 2016

Journal of Allergy and Clinical Immunology

View full text Add to dashboard Cite

Background Recent genome-wide association studies have identified single nucleotide polymorphisms in the protein αT-catenin (αT-cat; CTNNA3) that correlate with both steroid-resistant atopic asthma and asthmatic exacerbations. α-catenins are important mediators of cell-cell adhesion and αT-cat is predominantly expressed in cardiomyocytes. In the lung, αT-cat appears exclusively expressed in the cardiomyocytes surrounding pulmonary veins, but its contribution to atopic asthma remains unknown. Objective To understand the role of αT-cat in the pathogenesis of asthma. Methods We utilized αT-cat knockout mice and a house dust-mite extract (HDM) model of atopic asthma, with assessment by forced oscillation, bronchoalveolar lavage, and histologic analysis. Results We found that the genetic loss of αT-cat in mice largely attenuated HDM-induced airway inflammation and airway hyperresponsiveness to methacholine. Mice lacking αT-cat exposed to HDM extract showed reduced pulmonary vein inflammation, specifically near the large veins surrounded by cardiac cells. The proximity of airways to pulmonary veins correlated with the severity of airway goblet cell metaplasia, suggesting that pulmonary veins may influence the inflammatory milieu of adjacent airways. Loss of αT-cat led to the compensatory upregulation of αE-cat, which itself has a defined anti-inflammatory function. Conclusion These data mechanistically support previous clinical and genetic associations between αT-cat and the development of atopic asthma, and suggest that pulmonary veins may have an under-appreciated role in allergic airway inflammation.

show abstract

Dectin-2 sensing of house dust mite is critical for the initiation of airway inflammation

Cited by 60 publications

References 27 publications

Dectin-2 Regulates the Effector Phase of House Dust Mite–Elicited Pulmonary Inflammation Independently from Its Role in Sensitization

Dectin-2 Regulates the Effector Phase of House Dust Mite–Elicited Pulmonary Inflammation Independently from Its Role in Sensitization

Phosphoinositide 3-Kinase δ Regulates Dectin-2 Signaling and the Generation of Th2 and Th17 Immunity

The cardiomyocyte protein αT-catenin contributes to asthma through regulating pulmonary vein inflammation

Contact Info

Product

Resources

About