HOXA5 induces M2 macrophage polarization to attenuate carotid atherosclerosis by activating MED1

Abstract

Macrophage polarization is of great importance in the formation of atherosclerotic plaque. Homeobox A5 (HOXA5), one of the homeobox transcription factors, has been revealed to be closely associated with macrophage phenotype switching. This study aims to investigate the role of HOXA5 in carotid atherosclerosis (CAS). Herein, the role of HOXA5 was explored in polarized RAW264.7 macrophages in vitro and ApoE−/− mice in vivo. Interestingly, compared with that in M0 macrophages, both the mRNA and protein expression levels of HOXA5 were decreased in lipopolysaccharide (LPS)/interferon (IFN)‐γ‐induced M1 macrophages, while increased in IL‐4‐induced M2 macrophages. In addition, in the presence of IL‐4, HOXA5‐overexpressing RAW264.7 cells preferred to polarizing toward M2 phenotypes. Furthermore, we found that HOXA5 bound to the promoter region and activated the expression of mediator subunit 1 (MED1), a gene known to regulate macrophage differentiation. Knocking MED1 down inhibited HOXA5‐enhanced M2 macrophage polarization. In vivo, the CAS model was induced in ApoE−/− mouse fed with a Western‐type diet and placed a perivascular carotid collar. Decreased mRNA and protein expressions of HOXA5 were observed in carotid arteries of CAS mice. Forced overexpression of HOXA5 reduced intimal hyperplasia and lipid accumulation in carotid vessels, and it also promoted the polarization of macrophages to M2 subtypes. The expression of MED1 was decreased in atherosclerotic carotid vessels, while HOXA5 overexpression restored its change. Collectively, HOXA5 in carotid arteries is involved in the macrophage M1/M2 switching in atherosclerotic plaque, which may be associated with its transcriptional regulation of MED1.

Mechanosensitive Stem-Cell Genes and Klotho in Atherosclerotic Aortas: Regulating Spatially Deranged Expression Patterns Using Colchicine Regimens

“…In the abdominal aorta, hypercholesterolemic diet led to significant downregulation of the atheroprotective HOXA5 gene. Reduced HOXA5 expression has been implicated in intimal hyperplasia and derailed angiogenesis [ 17 ]. HOXA5 downregulation also promotes proatherogenic gene expression, extracellular matrix modification, and integrin alterations [ 40 ].…”

“…A growing body of literature has shown that dysregulation of Klotho and various stem-cell genes can occur due to shear stress [ 14 , 15 , 16 , 17 , 18 , 19 ]. This genetic derangement appears to orchestrate the development and progression of atherosclerosis [ 1 ].…”

Sevoflurane induces inflammation in primary hippocampal neurons by regulating Hoxa5/Gm5106/miR-27b-3p positive feedback loop

“…Hoxa5 usually plays tumor promotion roles in severe diseases such as breast cancer [ 25 ], acute myeloid leukemia [ 26 ] and colorectal cancer [ 27 ]. Notably, HOXA5 is also correlated to immune response involving M2 macrophage and TGF-β signaling pathways [ 28 ]. It is promising to investigate the effect of sevoflurane on immune system via HOXA5 connection, which will provide a deep explanation on neuroinflammation caused by sevoflurane.…”

Immunosuppressive tumor-associated macrophages expressing interlukin-10 conferred poor prognosis and therapeutic vulnerability in patients with muscle-invasive bladder cancer

“…The results showed that M1 macrophage markers (including CCR7, CCL5 and TNF) were significantly downregulated, while M2 macrophage markers (including CD163, MRC1, MSR1, VTCN1, ARG1, TGFB1, MMP14 and EGF) were upregulated in IL-10 + TAMs ( figure 4D ). Besides, several core transcription factor for M2 macrophage polarization including SOX7, MYC, HOXA5, TCF7L2, GATA3, RORA and TEAD4 were also enriched in IL-10 + TAMs compared with IL-10 - TAMs by single-cell regulatory network inference and clustering (SCENIC) analysis 24–26 ( figure 4E ). Importantly, to find a causative link between IL-10 + TAMs and exhausted T cells, we further conducted the cell communication analysis using scRNA-seq data and found a closed interaction between IL-10 + TAMs and exhausted CD8 + T cells with CellPhoneDB 27 ( figure 4F ).…”