Open AccessEndothelial toll‐like receptor 4 maintains lung integrity via epigenetic suppression of p16 INK4a
Author(s) -
Kim SoJin,
Shan Peiying,
Hwangbo Cheol,
Zhang Yi,
Min JinNa,
Zhang Xuchen,
Ardito Taylor,
Li Alfred,
Peng Tien,
Sauler Maor,
Lee Patty J.
Publication year - 2019
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12914
Subject(s) - biology , tlr4 , gene silencing , epigenetics , toll like receptor , lung , microbiology and biotechnology , cancer research , receptor , immunology , innate immune system , signal transduction , gene , genetics , medicine
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 p16 INK4a , a senescence‐associated gene. Lung Ec‐p16 INK4a ‐silencing prevented TLR4−/− induced emphysema, revealing a new functional role for p16 INK4a in lungs. TLR4 suppressed endogenous p16 INK4a 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.