Sirolimus-eluting airway stent reduces profibrotic Th17 cells and inhibits laryngotracheal stenosis

JCI Insight. 2023 Jun 8;8(11):e158456. doi: 10.1172/jci.insight.158456.


Laryngotracheal stenosis (LTS) is pathologic fibrotic narrowing of the larynx and trachea characterized by hypermetabolic fibroblasts and CD4+ T cell-mediated inflammation. However, the role of CD4+ T cells in promoting LTS fibrosis is unknown. The mTOR signaling pathways have been shown to regulate the T cell phenotype. Here we investigated the influence of mTOR signaling in CD4+ T cells on LTS pathogenesis. In this study, human LTS specimens revealed a higher population of CD4+ T cells expressing the activated isoform of mTOR. In a murine LTS model, targeting mTOR with systemic sirolimus and a sirolimus-eluting airway stent reduced fibrosis and Th17 cells. Selective deletion of mTOR in CD4+ cells reduced Th17 cells and attenuated fibrosis, demonstrating CD4+ T cells' pathologic role in LTS. Multispectral immunofluorescence of human LTS revealed increased Th17 cells. In vitro, Th17 cells increased collagen-1 production by LTS fibroblasts, which was prevented with sirolimus pretreatment of Th17 cells. Collectively, mTOR signaling drove pathologic CD4+ T cell phenotypes in LTS, and targeting mTOR with sirolimus was effective at treating LTS through inhibition of profibrotic Th17 cells. Finally, sirolimus may be delivered locally with a drug-eluting stent, transforming clinical therapy for LTS.

Keywords: Adaptive immunity; Fibrosis; Immunology; Pulmonology; T cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Constriction, Pathologic / drug therapy
  • Constriction, Pathologic / pathology
  • Drug-Eluting Stents*
  • Fibrosis
  • Humans
  • Laryngostenosis* / drug therapy
  • Laryngostenosis* / metabolism
  • Laryngostenosis* / pathology
  • Mice
  • Sirolimus / pharmacology
  • Sirolimus / therapeutic use
  • TOR Serine-Threonine Kinases
  • Th17 Cells / metabolism
  • Tracheal Stenosis* / drug therapy
  • Tracheal Stenosis* / metabolism


  • Sirolimus
  • TOR Serine-Threonine Kinases