Baby’s First Macrophage: Temporal Regulation of Hofbauer Cell Phenotype Influences Ligand-Mediated Innate Immune Responses across Gestation

Abstract

The importance of fetal placental macrophages (Hofbauer cell [HCs]) is underscored by their appearance 18 d postconception and maintenance through term; however, how human HCs evolve during healthy pregnancy and how microenvironment and ontogeny impact phenotype and function remain unknown. In this study, we comprehensively classify human HCs ex vivo, interrogate phenotypic plasticity, and characterize antiviral immune responses through gestation. Activated HCs were abundant in early pregnancy and decreased by term; molecular signatures emphasize inflammatory phenotypes early in gestation. Frequency of HCs with regulatory phenotypes remained high through term. Furthermore, term HCs exhibited blunted responses to stimulation, indicating reduced plasticity. IFN-l1 is a key placental IFN that appeared less protective than IFN-a, suggesting a potential weakness in antiviral immunity. Ligand-specific responses were temporally regulated: we noted an absence of inflammatory mediators and reduced antiviral gene transcription following RIG-I activation at term despite all HCs producing inflammatory mediators following IFN-g plus LPS stimulation. Collectively, we demonstrate sequential, evolving immunity as part of the natural history of HCs through gestation.

Does the human placenta express the canonical cell entry mediators for SARS-CoV-2?

“…Consistent with vertical transmission, AXL, the preferred receptor for ZIKV, was highly expressed by the cells of the human placenta and chorioamniotic membranes throughout gestation ( Figure 2 , ZIKV). The expression of CD209 was mainly found in the maternal and fetal macrophage subsets, as expected ( Svensson et al, 2011 ; Swieboda et al, 2020 ). Yet, the expression of TYRO3 was low ( Figure 2—figure supplement 2 ), consistent with the view that TAM receptors are not essential for ZIKV infection ( Hastings et al, 2017 ).…”

Does the human placenta express the canonical cell entry mediators for SARS-CoV-2?

“…2, ZIKV). The expression of CD206 was mainly found in the maternal and fetal macrophage subsets, as expected [89,90]. Yet, the expression of TYRO3 was low (Fig.…”

Phenotypic and functional characterization of first-trimester human placental macrophages, Hofbauer cells

“…Previous studies have yielded variable findings concerning the phenotype, cytokine secretion, and functions of HBCs ( Johnson and Chakraborty, 2012 ; Young et al, 2015 ; Pavlov et al, 2020 ; Loegl et al, 2016 ; Schliefsteiner et al, 2017 ; Swieboda et al, 2020 ), probably due to the failure to account for PAMM contamination, which we show is present in placental digests. Here, using our gating strategy for the isolation of placental myeloid cell populations, we find that steady-state HBCs secrete a range of factors that play a role in vascularization and the remodeling of blood vessels, such as VEGF-A, OPN, MMP-9, and TIMP-1 ( Johnson et al, 2003 ; Dai et al, 2009 ; Poggio et al, 2011 ; Luizon et al, 2014 ; Plaks et al, 2013 ).…”

“…The work presented in this study is limited to first-trimester samples. Previous studies have investigated the properties of HBCs across gestation ( Goldstein et al, 1988 ; Ingman et al, 2010 ; Swieboda et al, 2020 ; Pavlov et al, 2020 ). However, studies that used placental digests have not considered contamination with PAMM populations, and so interpretation of some of their findings is difficult.…”