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

Abstract:

: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.

journal_name

Aging Cell

journal_title

Aging cell

authors

Kim SJ,Shan P,Hwangbo C,Zhang Y,Min JN,Zhang X,Ardito T,Li A,Peng T,Sauler M,Lee PJ

doi

10.1111/acel.12914

subject

Has Abstract

pub_date

2019-06-01 00:00:00

pages

e12914

issue

3

eissn

1474-9718

issn

1474-9726

journal_volume

18

pub_type

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