| Autor: |
Kevin M. Motz, Ioan A. Lina, Idris Samad, Michael K. Murphy, Madhavi Duvvuri, Ruth J. Davis, Alexander Gelbard, Liam Chung, Yee Chan-Li, Samuel Collins, Jonathan D. Powell, Jennifer H. Elisseeff, Maureen R. Horton, Alexander T. Hillel |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
|
| Zdroj: |
JCI Insight, Vol 8, Iss 11 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2379-3708 |
| DOI: |
10.1172/jci.insight.158456 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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