Disrupting myeloid-specific LXRα phosphorylation promotes FoxM1 expression and modulates atherosclerosis by inducing macrophage proliferation

Abstract

Macrophages are key immune cells for the initiation and development of atherosclerotic lesions.However, the macrophage regulatory nodes that determine how lesions progress in response to dietary challenges are not fully understood. Liver X receptors (LXRs) are sterol-regulated transcription factors which play a central role in atherosclerosis by integrating cholesterol homeostasis and immunity. LXR pharmacological activation elicits a robust anti-atherosclerotic transcriptional program in macrophages that can be affected by LXRα S196 phosphorylation in vitro. To investigate the impact of these transcriptional changes in atherosclerosis development, we have generated mice carrying a Ser-to-Ala mutation in myeloid cells in the LDLR-deficient atherosclerotic background (M-S196A Ldlr-KO ). M-S196A Ldlr-KO mice fed a high fat diet exhibit increased atherosclerotic plaque burden and lesions with smaller necrotic cores and thinner fibrous caps. These diet-induced phenotypic changes are consistent with a reprogramed macrophage transcriptome promoted by LXRα-S196A during atherosclerosis development.Remarkably, expression of several proliferation-promoting factors including the proto-oncogene FoxM1 and its targets are induced by LXRα-S196A. This is consistent with increased proliferation of plaque-resident cells in M-S196A Ldlr-KO mice. Moreover, disrupted LXRα phosphorylation increases expression of phagocytic molecules resulting in increased apoptotic cell removal by macrophages, explaining the reduced necrotic cores. Finally, the macrophage transcriptome promoted by LXRα-S196A under dietary perturbation is markedly distinct from that revealed by LXR ligand activation, highlighting the singularity of this post-translational modification. Overall, our findings demonstrate that LXRα phosphorylation at S196 is an important determinant of atherosclerotic plaque development through selective changes in gene transcription that affect multiple pathways.

FOXM1 network in association with TREM1 suppression regulates NET formation in diabetic foot ulcers

“…Forkhead Box M1 (FOXM1) is a transcriptional activator of proliferation in an array of cell types and is overexpressed in many cancers (Liao et al, 2018). FOXM1 is also involved in the acute wound resolution of hyperoxic lung injury (Xia et al, 2015), as well as hepatocyte proliferation (Gieling et al, 2010) and leukocyte function (Ren et al, 2010;Gage et al, 2018) during toxic injury of the liver. Transgenic mice with FOXM1 deletion in the myeloid cell lineage also show significantly delayed liver repair (Kalin et al, 2011).…”