Dendritic and epithelial cell crosstalk in the lung: the impact of cell-specific Myd88 expression on consequent immune response to allergens

FARE Award Winner

Authors

• SY Thomas
• GS Whitehead
• KM Gowdy
• M Takaku
• X Xu
• JM Ward
• K Nakano
• H Nakano
• P Wade
• DN Cook

Abstract

Allergic asthma is an inflammatory disease of the airway stemming from inappropriate immune responses to inhaled environmental allergens. MYD88, the adaptor molecule for TLR and IL-1 family member signaling, is required for allergic sensitization through the airway. However, it is unclear which cell types in the lung must express Myd88 for allergic sensitization and how this cell-specific expression affects immune signaling in the airway. It has been proposed that airway epithelial cells (AECs) communicate with lung dendritic cells (DCs), but the molecular signals involved remain poorly understood. To address these questions, we generated mice lacking Myd88 in either AECs (AEC-KO), or in DCs (DC-KO) and studied the impact of these genetic changes on responses to various allergens. Following allergic sensitization and challenge, AEC-KO mice had significant reductions in eosinophils compared to WT mice, but retained large numbers of airway neutrophils. Conversely, DC-KO mice had marked reductions in Th17-associated cytokines and airway neutrophils, but retained eosinophilic inflammation. These surprising findings reveal that airway eosinophilia and neutrophilia are separable allergic events and suggest that new treatments can be developed to target specific forms of asthma. Analysis of RNA from purified DCs and AECs following sensitization revealed several genes (and gene families) whose expression in DCs depended on Myd88 signaling in AECs. Finally, ATAC-seq was used to study how DC chromatin structure is modulated by signals from AECs. Collectively, these observations identify specific molecular pathways that mediate crosstalk between AECs and DCs to promote allergic sensitization to inhaled allergens.

Scientific Focus Area: Immunology

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