Prophylactic Inhaled Pattern Recognition Receptor Agonists Reprogram Lung Epithelial Response and Prevent Type 2 Allergic Inflammation

Ntita, Mbaya, Kong, Celine Shuet Lin, Hassan, Dalia, Nayak, Richa, García, Jezreel Pantaleón, Wang, Yongxing, Chen, Jichao, Evans, Scott E (April 2026) Prophylactic Inhaled Pattern Recognition Receptor Agonists Reprogram Lung Epithelial Response and Prevent Type 2 Allergic Inflammation. European Journal of Immunology, 56 (4). e70172. ISSN 0014-2980

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Abstract

Prophylactic inhalation of the synergistic agents ODN M362 and Pam2CSK4 ("Pam2ODN") protects mice against allergic lung disease, including allergic inflammation caused by house dust mite (HDM). By preventing sensitization, Pam2ODN reduces HDM-induced eosinophilic and lymphocytic inflammation. How Pam2ODN affects interactions among lung epithelial cells, dendritic cells, and T cells to prevent eosinophilic lung inflammation remains unclear. In the present study, we show that a single inhaled dose of Pam2ODN before HDM sensitization reduces airway Th2 polarization without affecting Th1 or Treg responses. Furthermore, Pam2ODN pretreatment inhibits the recruitment of lung monocyte-derived dendritic cells (moDCs) and conventional Type 2 dendritic cells (DC2s), while preventing the HDM-induced decrease in conventional Type 1 dendritic cells (DC1s). Bulk RNA-seq of the whole lung reveals that Pam2ODN pretreatment restricts the expression of proinflammatory transcripts induced by HDM sensitization. This tolerogenic effect is also reflected at the single-cell level in lung epithelial cells, where proinflammatory transcripts, pathways, and chromatin accessibility are inhibited. These results indicate that Pam2ODN reprograms lung epithelial cells to attenuate allergen-induced Th2-promoting cytokines and DCs while maintaining the population of protective DC1s. These findings suggest a strategy to mitigate chronic allergic lung diseases.

Item Type:	Paper
Subjects:	diseases & disorders diseases & disorders > immune system diseases > hypersensitivity diseases & disorders > immune system diseases
CSHL Authors:	Hassan, Dalia
Communities:	CSHL labs > Vakoc lab CSHL Post Doctoral Fellows
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	April 2026
Date Deposited:	30 Mar 2026 13:07
Last Modified:	30 Mar 2026 13:07
PMCID:	PMC13022946
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/42128

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