Severe preeclampsia (sPE) is a pregnancy-specific disease that affects 2–8% of all pregnancies (Jimmy Espinoza et al., 2020), and there are critical pathological changes in maternal-fetal immune stress and the inflammation response (Tenório et al., 2019, Goldstein et al., 2020, Sun et al., 2021, Harmon et al., 2016). Decidual immune cells, such as natural killer cells, T cells and macrophages are the main populations (Tessier et al., 2015, Faas and de Vos, 2017, Owen and Mohamadzadeh, 2013) that suppress inflammation and promote immune privilege during normal pregnancy (Erlebacher, 2013, Redman and Sargent, 2010, van Mourik et al., 2009). Among them, decidual macrophages (dMs) are highly associated with inflammatory responses in the placenta and systemic endothelial injury (Harmon et al., 2016, Vishnyakova et al., 2019, Renaud and Graham, 2008, Ning et al., 2016, Faas et al., 2014, Li et al., 2016) through the secretion of pro- or anti-inflammatory cytokines (Renaud and Graham, 2008, Ning et al., 2016, Xu et al., 2021, Nagamatsu and Schust, 2010) that can cause positive feedback effects on inflammatory storms (Harmon et al., 2016, Taylor and Colgan, 2017, Conrad and Benyo, 1997, Sharma et al., 2007, Aggarwal et al., 2019). Anti-inflammatory dMs produce less TNFα, IL6, and IL8 in normal pregnancy, resulting in immune tolerance (Tenório et al., 2019, Erlebacher, 2013, Hsu and Nanan, 2014). However, during PE development, dMs showed few immunosuppressive characteristics (Xu et al., 2021, Nagamatsu and Schust, 2010, Schonkeren et al., 2011, Yao et al., 2019) as a result of oxidative stress or interactions with stressful trophoblasts under hypoxic conditions (Xu et al., 2021, Przybyl et al., 2016). Finally, immune imbalance and excessive inflammation occur, destroying the systemic vascular endothelium and leading to preeclampsia. Overall, there is an urgent need to explore how dMs are modulated to repress inflammation.

Based on placental single-cell sequencing, several pairs of antigens/receptors between trophoblasts and decidual immune cells (Xu et al., 2017, Vento-Tormo et al., 2018) have been reported to be associated with immune privilege. Programmed death ligand (PDL1), which is widely expressed in maternal-fetal interface cells (Xu et al., 2017, Taglauer et al., 2008, Petroff et al., 2003) and even cells in peripheral blood (Meggyes et al., 2019), can bind to the programmed death protein (PD1) on the surface of immune cells to suppress inflammation (Lanza et al., 2019). During the normal gestational process, trophoblast-derived PDL1 is maximally expressed during early pregnancy and then gradually diminishes until delivery (Xu et al., 2017, Taglauer et al., 2008) and seems to respond to stress variations (Taylor and Colgan, 2017). PDL1/Galectin-9 can inhibit M1 polarization and alleviate symptoms of LPS-induced PE-like rats through PD1/Tim3 (Hu et al., 2022).

Abnormally low levels of PDL1 in the placenta could lead to an increased ratio of Th17/Treg or Th1/Th2 cells and regulate the mTOR/PI3K pathway, causing immune imbalance (Meggyes et al., 2019, Tian et al., 2016, Zhang et al., 2018). In recurrent miscarriage (RM), an altered PDL1/PD1 pathway has been shown to reverse the differentiation of peripheral blood macrophages (Zhang and Hu, 2019). Moreover, trophoblast-derived PDL1 can vary according to hypoxia and even exist in the peripheral circulation as soluble or extracellular PDL1, such as exosomes (Xu et al., 2017, Noman et al., 2014, Okuyama et al., 2019). However, there is no convincing evidence on how the fetal trophoblast PDL1 interacts with dMs to influence the systemic inflammatory response.

To investigate how trophoblast-derived PDL1 influences dM-related inflammation in sPE, we verified PDL1/PD1 expression and inflammation at the maternal-fetal interface. Then, we examined the inhibitory effect of PDL1/PD1 on inflammation through in vitro and in vivo experiments. Our team initially found elevated expression of PDL1/PD1 at the sPE placental interface, which was accompanied by increased inflammation. Next, we identified that trophoblast-PDL1 crosstalked with macrophage-PD1 to inhibit inflammation under hypoxic coculture conditions and that the TNFα/p38/NFκB pathway could be a possible downstream target. Then, we examined the protective effect of PDL1 on blood pressure and placental pathologies in PE-like mice. Our study showed for the first time how EVT-derived PDL1 rescued macrophage-related inflammation under stress conditions and provided a novel immunological adaptive mechanism in sPE placental injuries.