Histone deacetylase 9 deficiency exaggerates uterine M2 macrophage polarization

Abstract

The maternal‐foetal interface is an immune‐privileged site where the semi‐allogeneic embryo is protected from attacks by the maternal immune system. Uterine macrophages are key players in establishing and maintaining pregnancy, and the dysregulation of the M1‐M2 subpopulation balance causes abortion. We separated two distinct mouse uterine macrophage subpopulations during early pregnancy, CD45+F4/80+CD206− M1‐like (M1) and CD45+F4/80+CD206+ M2‐like (M2) cells. The M1 preponderance was significantly exaggerated at 6 hours after lipopolysaccharide (LPS) treatment, and adoptive transfer of M2 macrophages partially rescued LPS‐induced abortion. RNA sequencing analysis of mouse uterine M2 versus M1 revealed 1837 differentially expressed genes (DEGs), among which 629 was up‐regulated and 1208 was down‐regulated. Histone deacetylase 9 (Hdac9) was one of the DEGs and validated to be significantly up‐regulated in uterine M2 as compared with M1. Remarkably, this differential expression profile between M1 and M2 was also evident in primary splenic macrophages and in vitro polarized murine peritoneal, bone marrow–derived and RAW 264.7 macrophages. In Hdac9/HDAC9 knockout RAW 264.7 and human THP‐1–derived macrophages, the expression of M1 differentiation markers was unchanged or decreased whereas M2 markers were increased compared with the wild‐type cells, and these effects were unrelated to compromised proliferation. Furthermore, Hdac9/HDAC9 ablation significantly enhanced the phagocytosis of fluorescent microspheres in M2 Raw 264.7 cells yet decreased the capacity of THP‐1‐derived M1 macrophages. The above results demonstrate that Hdac9/HDAC9 deficiency exaggerates M2 macrophage polarization in mouse and human macrophages, which may provide clues for our understanding of the epigenetic regulation on macrophage M1/M2 polarization in maternal‐foetal tolerance.

Cytochrome P450 26A1 Modulates the Polarization of Uterine Macrophages During the Peri-Implantation Period

“…In this study, we first detected the expression of Cyp26a1 in several different types of macrophages and we found that this gene was significantly upregulated in M1 as compared with M2 of GD6 uterine macrophages, Raw264.7 and iBMDM. The RNA-seq of uterine macrophages in another study also showed that the expression of Cyp26a1 in M1 was significantly higher than that of M2 in mice ( 47 ). However, it should be noted that we did not detect the expression of Cyp26a1 in M1 and M2 of BMDM, GD6 spleen macrophages and THP-1.…”

Epigenetic regulation of macrophage polarization in wound healing

“…Loss of HDAC3 promotes macrophage skewing toward the M2 phenotype after stimulation by Th2 cytokines [ 61 ]. Similar to HDAC3, HDAC9 also inhibits M2 polarization by deacetylating the PPAR γ promoter [ 62 , 63 ]. Silent information regulator 2 homolog (SIRT1) is a negative regulator of M1 polarization via inhibition of the NF-κB pathway [ 64 ].…”

Acetylation in Tumor Immune Evasion Regulation

“…HDAC7 blocks the induction of genes that involved in macrophage immunity, phagocytosis, inflammation and cytokine production ( Barneda-Zahonero et al, 2013 ). Besides, in uterine macrophages, HDAC9 deficiency promotes M2 macrophage polarization ( Liu et al, 2021 ). HDAC9 also enhance immune response via enhancing dendritic cell antigen presentation and CD8+T cell TME infiltration ( Ning et al, 2020 ).…”