Rhinovirus-induced CCL17 and CCL22 in Asthma Exacerbations and Differential Regulation by STAT6

Am J Respir Cell Mol Biol. 2021 Mar;64(3):344-356. doi: 10.1165/rcmb.2020-0011OC.


The interplay of type-2 inflammation and antiviral immunity underpins asthma exacerbation pathogenesis. Virus infection induces type-2 inflammation-promoting chemokines CCL17 and CCL22 in asthma; however, mechanisms regulating induction are poorly understood. By using a human rhinovirus (RV) challenge model in human airway epithelial cells in vitro and mice in vivo, we assessed mechanisms regulating CCL17 and CCL22 expression. Subjects with mild to moderate asthma and healthy volunteers were experimentally infected with RV and airway CCL17 and CCL22 protein quantified. In vitro airway epithelial cell- and mouse-RV infection models were then used to define STAT6- and NF-κB-mediated regulation of CCL17 and CCL22 expression. Following RV infection, CCL17 and CCL22 expression was higher in asthma, which differentially correlated with clinical and immunological parameters. Air-liquid interface-differentiated primary epithelial cells from donors with asthma also expressed higher levels of RV-induced CCL22. RV infection boosted type-2 cytokine-induced STAT6 activation. In epithelial cells, type-2 cytokines and STAT6 activation had differential effects on chemokine expression, increasing CCL17 and suppressing CCL22, whereas NF-κB promoted expression of both chemokines. In mice, RV infection activated pulmonary STAT6, which was required for CCL17 but not CCL22 expression. STAT6-knockout mice infected with RV expressed increased levels of NF-κB-regulated chemokines, which was associated with rapid viral clearance. Therefore, RV-induced upregulation of CCL17 and CCL22 was mediated by NF-κB activation, whereas expression was differentially regulated by STAT6. Together, these findings suggest that therapeutic targeting of type-2 STAT6 activation alone will not block all inflammatory pathways during RV infection in asthma.

Keywords: STAT6; asthma; rhinovirus.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Adolescent
  • Adult
  • Animals
  • Asthma / pathology*
  • Asthma / virology*
  • Biomarkers / metabolism
  • Chemokine CCL17 / metabolism*
  • Chemokine CCL22 / metabolism*
  • Chemokines / metabolism
  • Disease Progression*
  • Epithelial Cells / metabolism
  • Female
  • Humans
  • Kinetics
  • Lung / pathology
  • Lung / virology
  • Male
  • Mice, Inbred BALB C
  • Middle Aged
  • NF-kappa B / metabolism
  • Rhinovirus / physiology*
  • STAT6 Transcription Factor / metabolism*
  • Tissue Donors
  • Young Adult


  • Biomarkers
  • CCL17 protein, human
  • CCL22 protein, human
  • Chemokine CCL17
  • Chemokine CCL22
  • Chemokines
  • NF-kappa B
  • STAT6 Transcription Factor
  • STAT6 protein, human