Atypical Chemokine Receptor ACKR2 Mediates Chemokine Scavenging by Primary Human Trophoblasts and Can Regulate Fetal Growth, Placental Structure, and Neonatal Mortality in Mice

Abstract

Inflammatory chemokines produced in the placenta can direct the migration of placental leukocytes using chemokine receptors that decorate the surface of these cells. Fetal trophoblasts can also express receptors for inflammatory chemokines, and they are one of the few cell types that express atypical chemokine receptor 2 (ACKR2), previously known as D6. ACKR2 binds many inflammatory CC chemokines but cannot stimulate cell migration or activate signaling pathways used by conventional chemokine receptors. Existing evidence suggests that ACKR2 is a specialized chemokine scavenger, but its function in primary human trophoblasts has not been explored. In mice, ACKR2 is thought to be dispensable for the reproductive success of unchallenged females that have conceived naturally, but it can suppress inflammation-induced abortion and aid the survival of implanted allogeneic embryos. In this article, we demonstrate that cultured primary human trophoblasts express ACKR2 far more strongly than genes encoding conventional receptors for inflammatory CC chemokines. Moreover, these cells are capable of the rapid internalization and efficient scavenging of extracellular chemokine, and this is mediated by ACKR2. We also report that in unchallenged DBA/1j mice, Ackr2 deficiency increases the incidence of stillbirth and neonatal death, leads to structural defects in the placenta, and can decrease fetal weight. Loss of Ackr2 specifically from fetal cells makes a key contribution to the placental defects. Thus, primary human trophoblasts use ACKR2 to scavenge chemokines, and ACKR2 deficiency can cause abnormal placental structure and reduced neonatal survival.

Distinctive phenotypes and functions of innate lymphoid cells in human decidua during early pregnancy

“…They also secrete MIP1α (CCL3) and MIP1β (CCL4) which can bind to CCR1 and the scavenging receptor, ACKR2 (D6), both expressed by EVT 64,65 . Loss of Ackr2 in murine fetal cells leads to placental defects and fetal death 66 . To investigate the effects of cytokines and chemokines derived from dILC subsets in humans requires in vitro experimental models.…”

Reconstructing the human first trimester fetal–maternal interface using single cell transcriptomics

“…5e). ACKR2 acts as a decoy 275 receptor, effectively putting a brake on the inflammatory response 35,36 . CCL5 also binds the chemokine receptor CCR1 expressed by EVT, and may regulate EVT migration into the decidua 37 .…”

Overview and potential unifying themes of the atypical chemokine receptor family

“…All ACKRs are expressed on epithelial tissues of barrier organs (ACKR1 [60,82,83]; ACKR2 [84,85]; ACKR3 [20,86]; ACKR4 [48,55,56,[87][88][89][90][91][92]; ackr5 [93]) and on trophoblast cells, the epithelial cells of fetal origin that form the physical placental barrier between the mother and the developing conceptus (ACKR1 [94]; ACKR2 [94][95][96][97]; ACKR3 [97][98][99][100]; ACKR4 [25,94]). No data are available on the expression of ackr5 in placenta, although elevated levels of its ligand chemerin have been reported recently [101].…”