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Aging Cell. 2019 Jun;18(3):e12914. doi: 10.1111/acel.12914. Epub 2019 Feb 20.

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

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Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
Division of Applied Life Science (BK21 Plus), PMBBRC, Division of Life Science, College of National Sciences, Gyeongsang National University, Jinju, Korea.
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
Bone Imaging Research Core, University of California, San Francisco (UCSF), San Francisco, California.
Department of Medicine, Cardiovascular Research Institute, UCSF, San Francisco, California.


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.


HDAC2; aging; cellular senescence; emphysema; p16INK4a; toll-like receptor 4

[Available on 2019-06-01]
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