Endothelial toll-like receptor 4 maintains lung integrity via epigenetic suppression of p16INK4a.

Journal Article (Journal Article)

We previously reported that the canonical innate immune receptor toll-like receptor 4 (TLR4) is critical in maintaining lung integrity. However, the molecular mechanisms via which TLR4 mediates its effect remained unclear. In the present study, we identified distinct contributions of lung endothelial cells (Ec) and epithelial cells TLR4 to pulmonary homeostasis using genetic-specific, lung- and cell-targeted in vivo methods. Emphysema was significantly prevented via the reconstituting of human TLR4 expression in the lung Ec of TLR4-/- mice. Lung Ec-silencing of TLR4 in wild-type mice induced emphysema, highlighting the specific and distinct role of Ec-expressed TLR4 in maintaining lung integrity. We also identified a previously unrecognized role of TLR4 in preventing expression of p16INK4a , a senescence-associated gene. Lung Ec-p16INK4a -silencing prevented TLR4-/- induced emphysema, revealing a new functional role for p16INK4a in lungs. TLR4 suppressed endogenous p16INK4a expression via HDAC2-mediated deacetylation of histone H4. These findings suggest a novel role for TLR4 in maintaining of lung homeostasis via epigenetic regulation of senescence-related gene expression.

Full Text

Duke Authors

Cited Authors

  • Kim, S-J; Shan, P; Hwangbo, C; Zhang, Y; Min, J-N; Zhang, X; Ardito, T; Li, A; Peng, T; Sauler, M; Lee, PJ

Published Date

  • June 2019

Published In

Volume / Issue

  • 18 / 3

Start / End Page

  • e12914 -

PubMed ID

  • 30790400

Pubmed Central ID

  • PMC6516428

Electronic International Standard Serial Number (EISSN)

  • 1474-9726

Digital Object Identifier (DOI)

  • 10.1111/acel.12914


  • eng

Conference Location

  • England