Endothelial immune activation programs cell-fate decisions and angiogenesis by inducing DLL4 through TLR4-ERK-FOXC2 signalling

Abstract

Endothelial cells (EC) mediate a specific and robust immune response to bacteria in sepsis through the activation of Toll-Like Receptor (TLR) signalling. The mechanisms by which bacterial ligands released during sepsis program endothelial cell (EC) specification and altered angiogenesis remain unclear. We postulated that the Forkhead box protein C2 (FOXC2) transcriptional factor directs EC cell-fate decisions and angiogenesis during TLR signalling. In human lung EC, LPS induced ERK phosphorylation, FOXC2, and DLL4 expression in a TLR4-dependent manner. LPS mediated ERK phosphorylation resulted in FOXC2-ERK protein ligation, ERK-dependent FOXC2 serine and threonine phosphorylation, and subsequent activation of DLL4 gene expression. Chemical inhibition of ERK or ERK-2 dominant negative transfection disrupted LPS-mediated FOXC2 phosphorylation and transcriptional activation of FOXC2. FOXC2-siRNA or ERK-inhibition attenuated LPS-induced DLL4 expression and angiogenic sprouting in vitro. In vivo, intraperitoneal LPS induced ERK and FOXC2 phosphorylation, FOXC2 binding to DLL4 promoter, and FOXC2/DLL4 expression in the lung. ERK-inhibition suppressed LPS-induced FOXC2 phosphorylation, FOXC2-DLL4 promoter binding, and induction of FOXC2 and DLL4 in mouse lung EC. LPS induced aberrant retinal angiogenesis and DLL4 expression in neonatal mice, which was attenuated with ERK-inhibition. FOXC2+/- mice treated with LPS showed a mitigated increase in FOXC2 and DLL4 compared to FOXC2+/+ mice. These data reveal a new mechanism (TLR4-ERK-FOXC2-DLL4) by which sepsis-induced EC TLR signalling programs EC specification and altered angiogenesis.

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