Epithelial Immunomodulation by Aerosolized Toll-Like Receptor Agonists Prevents Allergic Inflammation in Airway Mucosa in Mice

Authors

David L Goldblatt
Gabriella Valverde Ha
Shradha Wali
Vikram V Kulkarni
Michael K Longmire
Ana M Jaramillo
Rosha P Chittuluru
Adrienne Fouts
Margarita Martinez-Moczygemba
Jonathan T Lei
David P Huston
Michael J Tuvim
Burton F Dickey
Scott E Evans

Publication Date

1-1-2022

Journal

Frontiers in Pharmacology

Abstract

Allergic asthma is a chronic inflammatory respiratory disease associated with eosinophilic infiltration, increased mucus production, airway hyperresponsiveness, and airway remodeling. Epidemiologic data reveal that the prevalence of allergic sensitization and associated diseases has increased in the twentieth century. This has been hypothesized to be partly due to reduced contact with microbial organisms (the hygiene hypothesis) in industrialized society. Airway epithelial cells, once considered a static physical barrier between the body and the external world, are now widely recognized as immunologically active cells that can initiate, maintain, and restrain inflammatory responses, such as those that mediate allergic disease. Airway epithelial cells can sense allergens via expression of myriad Toll-like receptors (TLRs) and other pattern-recognition receptors. We sought to determine whether the innate immune response stimulated by a combination of Pam2CSK4 (“Pam2”, TLR2/6 ligand) and a class C oligodeoxynucleotide ODN362 (“ODN”, TLR9 ligand), when delivered together by aerosol (“Pam2ODN”), can modulate the allergic immune response to allergens. Treatment with Pam2ODN 7 days before sensitization to House Dust Mite (HDM) extract resulted in a strong reduction in eosinophilic and lymphocytic inflammation. This Pam2ODN immunomodulatory effect was also seen using Ovalbumin (OVA) and A. oryzae (Ao) mouse models. The immunomodulatory effect was observed as much as 30 days before sensitization to HDM, but ineffective just 2 days after sensitization, suggesting that Pam2ODN immunomodulation lowers the allergic responsiveness of the lung, and reduces the likelihood of inappropriate sensitization to aeroallergens. Furthermore, Pam2 and ODN cooperated synergistically suggesting that this treatment is superior to any single agonist in the setting of allergen immunotherapy.

Keywords

toll-like receptors, allergic asthma, allergen immunotherapy, innate immunity, lung epithelial cells, allergen tolerance

DOI

10.3389/fphar.2022.833380

PMID

36105216

PMCID

PMC9464972

PubMedCentral® Posted Date

8-29-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes