Dysfunctional neutrophil type 1 interferon responses in preschool children with recurrent wheezing and IL-4-mediated aeroallergen sensitization

Anne M Fitzpatrick; Min Huang; Ahmad F Mohammad; Susan T Stephenson; Rishikesan Kamaleswaran; Jocelyn R Grunwell

doi:10.1016/j.jacig.2024.100229

Dysfunctional neutrophil type 1 interferon responses in preschool children with recurrent wheezing and IL-4-mediated aeroallergen sensitization

J Allergy Clin Immunol Glob. 2024 Feb 13;3(2):100229. doi: 10.1016/j.jacig.2024.100229. eCollection 2024 May.

Authors

Anne M Fitzpatrick^{1

2}, Min Huang³, Ahmad F Mohammad¹, Susan T Stephenson¹, Rishikesan Kamaleswaran³, Jocelyn R Grunwell^{1

4}

Affiliations

¹ Department of Pediatrics, Emory University, Atlanta, Ga.
² Division of Pulmonary Medicine, Children's Healthcare of Atlanta, Atlanta, Ga.
³ Department of Biomedical Informatics, Emory University, Atlanta, Ga.
⁴ Division of Critical Care Medicine, Children's Healthcare of Atlanta, Atlanta, Ga.

Abstract

Background: The innate mechanisms associated with viral exacerbations in preschool children with recurrent wheezing are not understood.

Objective: We sought to assess differential gene expression in blood neutrophils from preschool children with recurrent wheezing, stratified by aeroallergen sensitization, at baseline and after exposure to polyinosinic:polycytidylic acid (poly(I:C)) and also to examine whether poly(I:C)-stimulated blood neutrophils influenced airway epithelial gene expression.

Methods: Blood neutrophils were purified and cultured overnight with poly(I:C) and underwent next-generation sequencing with Reactome pathway analysis. Primary human small airway epithelial cells were treated with poly(I:C)-treated neutrophil culture supernatants and were analyzed for type 1 interferon gene expression with a targeted array. Symptoms and exacerbations were assessed in participants over 12 months.

Results: A total of 436 genes were differently expressed in neutrophils from children with versus without aeroallergen sensitization at baseline, with significant downregulation of type 1 interferons. These type 1 interferons were significantly upregulated in sensitized children after poly(I:C) stimulation. Confirmatory experiments demonstrated similar upregulation of type 1 interferons in IL-4-treated neutrophils stimulated with poly(I:C). Poly(I:C)-treated neutrophil supernatants from children with aeroallergen sensitization also induced a type 1 interferon response in epithelial cells. Children with aeroallergen sensitization also had higher symptom scores during exacerbations, and these symptom differences persisted for 3 days after prednisolone treatment.

Conclusions: Type 1 interferon responses are dysregulated in preschool children with aeroallergen sensitization, which is in turn associated with exacerbation severity. Given the importance of type 1 interferon signaling in viral resolution, additional studies of neutrophil type 1 interferon responses are needed in this population.

Keywords: Asthma; endotype; innate immunity; neutrophil; next-generation sequencing; phenotype; respiratory infection; sensitization; type 1 interferon; wheezing.