Impaired trophoblast efferocytosis by decidual macrophages in early-onset preeclampsia
Preeclampsia (PE) is a hypertensive disorder of pregnancy associated with inadequate trophoblast invasion, impaired spiral artery remodelling and increased trophoblast apoptosis, leading to malplacentation. Decidual macrophages are through to be key in clearing these apoptotic cells via efferocytosis, a process that normally promotes an anti-inflammatory phenotype. In PE, however, transcriptomic studies have shown that decidual macrophages exhibit a pro-inflammatory phenotype, suggesting their ability to efferocytose may be impaired. This study investigated whether PE alters ex vivo decidual macrophage function in placentas obtained from healthy pregnancies (n=11) or with early-onset PE (n=9). Macrophages isolated from both the decidua basalis and decidua parietalis of PE placentas demonstrated significantly reduced efferocytosis of apoptotic trophoblasts compared to healthy controls, accompanied by increased release of CXCL-8 and IL-6. Similarly, phagocytosis of Streptococcus agalactiae was significantly impaired by both macrophage subtypes. Analysis of macrophage scavenger receptors revealed that efferocytic macrophages upregulate receptors for eat me signals, whereas non-efferocytic macrophages fail to do so. These findings demonstrate that decidual macrophages in the preeclamptic placenta exhibit impaired efferocytosis and phagocytosis, which may contribute to the accumulation of apoptotic trophoblasts and increased pro-inflammatory signaling. Further analysis of this defective function is vital to identify novel immunomodulatory treatments for PE. Graphical abstractIn healthy pregnancy, decidual macrophage efferocytosis of apoptotic trophoblasts prevents inflammation through release of anti-inflammatory IL-10. In early-onset preeclampsia, failure to efferocytose causes a build up of apoptotic trophoblasts, and promotes inflammation through release of pro-inflammatory CXCL-8 and IL-6. Targeting decidual macrophage function may be beneficial in preeclampsia. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=164 SRC="FIGDIR/small/708195v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@ca7b24org.highwire.dtl.DTLVardef@15a9289org.highwire.dtl.DTLVardef@14a6631org.highwire.dtl.DTLVardef@17b4ff1_HPS_FORMAT_FIGEXP M_FIG C_FIG