Serum Amyloid A in the Placenta and Its Role in Trophoblast Invasion

Abstract

The serum amyloid A (SAA) protein is known to function in the acute phase response and immunoregulation. Recently, SAA has been shown to be involved in cell proliferation, differentiation and migratory behavior in different cell types. Here, we evaluated whether exogenous SAA could influence trophoblast invasion and differentiation using both the trophoblast-like BeWo cell line and fully differentiated human extravillous trophoblast cells (EVT) isolated from term placentae. SAA stimulated BeWo cell invasion, as measured in Matrigel invasion assays, and induced metalloprotease mRNA expression and activity. Given that BeWo cells express Toll-like receptor 4 (TLR4), a known receptor for SAA, we examined the role of TLR4 in SAA-induced invasion using a TLR4 neutralizing antibody. We also tested whether SAA could affect markers of trophoblast syncytialization in BeWo cells. We observed that SAA decreased βhCG secretion and did not influence trophoblast syncytialization. Using EVT cells isolated from human term basal plates, we confirmed that SAA at 1 and 10 µg/mL doubled EVT invasion in a TLR4-dependent manner, but at 20 µg/mL inhibited EVT cells invasiveness. In addition, we observed that SAA was expressed in both BeWo cells and human term placentae, specifically in the syncytiotrophoblast, decidual cells and EVT. In conclusion, SAA was identified as a molecule that functions in the placental microenvironment to regulate metalloprotease activity and trophoblast invasion, which are key processes in placentation and placental homeostasis.

De novo Synthesis of SAA1 in the Placenta Participates in Parturition

“…Studies in trophoblast-derived cell lines and extravillous trophoblasts indicate a role of SAA in trophoblast invasion but not in syncytialization (28,29). Here, our findings that SAA1 induced the expression of a number of inflammatory factors including IL-1β, IL-8, TNF-α, and PGF2α are an indicator of involvement of SAA1 in inflammatory reactions in the placenta, which is in line with its inflammatory actions in fetal membranes.…”

“…However, non-hepatic tissues including fetal membranes can also synthesize SAA1 (17,18). Previous studies have demonstrated the presence of SAA transcripts in placental trophoblast cell lines and possibly its protein in placental villous trophoblasts (28,29). In the present study, we provided evidence that SAA1 could indeed be synthesized in the human placenta because both SAA1 mRNA and protein were present in placenta villous trophoblasts.…”

Retracted: Maternal serum amyloid A level as a novel marker of primary unexplained recurrent early pregnancy loss

“…The investigators also found that SAA was expressed in the decidual cells, syncytiotrophoblasts, and extravillous cytotrophoblasts. Consequently, when present at low concentrations, SAA functions in key processes required for placental homeostasis and placentation, a sequence of events that is disturbed by increasing concentrations of SAA …”

“…Multivariable logistic regression analysis identified SAA level as an independent indicator of this pregnancy complication.The elevated SAA levels observed in the present study might reflect a reversed physiological role for this protein in primary unexplained REPL, leading to impaired trophoblastic invasion and syncytialization.The levels of SAA were reported to increase in the first-trimester trophoblast (at 10-12 weeks), suggesting an important function in early fetal development; 6 however, the magnitude of this increase was not demonstrated, nor was its exact physiological role.At physiological levels, SAA modulates trophoblastic invasion into the decidua (a necessary step during the early stages of pregnancy stages) via activation of toll-like receptor 4, and maintains a functional balance between proinflammatory and anti-inflammatory cytokines for feto-maternal tolerance 3. By contrast, increased levels of SAA are associated with impaired trophoblastic invasion and syncytialization 3. One study used extravillous cytotrophoblasts and a trophoblast-like human cell line to examine the influence of exogenous SAA on trophoblastic migration, invasion and differentiation.…”

Extracellular matrix remodeling effects of serum amyloid A1 in the human amnion: Implications for fetal membrane rupture

“…Several receptors have been identified to mediate the actions of SAA1, including the N ‐formyl peptide receptor 2 (FPR2), Toll‐like receptor 2 (TLR2), and Toll‐like receptor 4 (TLR4) . Notably, SAA1 may also participate in extracellular matrix (ECM) remodeling to aid in the migration of neutrophils, trophoblasts, and tumour cells . However, the mechanisms underlying the ECM remodeling effects of SAA1 remain mostly elusive.…”