Distinct Epithelial-Innate Immune Cell Transcriptional Circuits Underlie Airway Hyperresponsiveness in Asthma

Ryan C. Murphy, Ying Lai, Matthew Liu, Taha Al-Shaikhly, Matthew C. Altman, William A. Altemeier, Charles W. Frevert, Jason S. Debley, Adrian M. Piliponsky, Steven F. Ziegler, Sina A. Gharib, Teal S. Hallstrand

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Rationale: Indirect airway hyperresponsiveness (AHR) is a highly specific feature of asthma, but the underlying mechanisms responsible for driving indirect AHR remain incompletely understood. Objectives: To identify differences in gene expression in epithelial brushings obtained from individuals with asthma who were characterized for indirect AHR in the form of exercise-induced bronchoconstriction (EIB). Methods: RNA-sequencing analysis was performed on epithelial brushings obtained from individuals with asthma with EIB (n = 11) and without EIB (n = 9). Differentially expressed genes (DEGs) between the groups were correlated with measures of airway physiology, sputum inflammatory markers, and airway wall immunopathology. On the basis of these relationships, we examined the effects of primary airway epithelial cells (AECs) and specific epithelial cell–derived cytokines on both mast cells (MCs) and eosinophils (EOS). Measurements and Main Results: We identified 120 DEGs in individuals with and without EIB. Network analyses suggested critical roles for IL-33–, IL-18–, and IFN-g–related signaling among these DEGs. IL1RL1 expression was positively correlated with the density of MCs in the epithelial compartment, and IL1RL1, IL18R1, and IFNG were positively correlated with the density of intraepithelial EOS. Subsequent ex vivo modeling demonstrated that AECs promote sustained type 2 (T2) inflammation in MCs and enhance IL-33–induced T2 gene expression. Furthermore, EOS increase the expression of IFNG and IL13 in response to both IL-18 and IL-33 as well as exposure to AECs. Conclusions: Circuits involving epithelial interactions with MCs and EOS are closely associated with indirect AHR. Ex vivo modeling indicates that epithelial-dependent regulation of these innate cells may be critical in indirect AHR and modulating T2 and non-T2 inflammation in asthma.

Original languageEnglish (US)
Pages (from-to)1565-1575
Number of pages11
JournalAmerican journal of respiratory and critical care medicine
Issue number12
StatePublished - Jun 2023

All Science Journal Classification (ASJC) codes

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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