Cutting‐Edge Report: TLR10 Plays a Role in Mediating Bacterial Peptidoglycan‐Induced Trophoblast Apoptosis

Abstract

Problem There is a strong correlation between intrauterine bacterial infection and preterm labor. While inflammation is a common mechanism, certain pathogens may trigger placental apoptosis. TLR2 activation by gram-positive bacterial peptidoglycan (PDG) induces first trimester trophoblast apoptosis and decreased IL-6 secretion. This is dependent upon the presence of TLR1 and the absence of TLR6, both TLR2 co-receptors. Since TLR10 is also a TLR2 co-receptor, the objective of this study was to determine its expression and function in the trophoblast. Method of Study First and third trimester human placental tissue and isolated trophoblast were evaluated for TLR10 expression. A first trimester human trophoblast cell line, stably transfected with a TLR10 dominant negative (TLR10-DN) or vector control was treated with or without PDG and analyzed for apoptosis and IL-6. Results TLR10 was expressed by trophoblasts during the first and third trimesters of pregnancy. PDG-induced trophoblast caspase-3 activity was inhibited by the presence of the TLR10-DN. The presence of the TLR10-DN had no effect on PDG- reduction in trophoblast IL-6 secretion. Conclusion This study demonstrates that trophoblast TLR10 plays a role in promoting apoptosis triggered by gram-positive bacterial components, and suggests that TLR10 may regulate the balance between trophoblast survival and cell death.

Human TLR10 is an anti-inflammatory pattern-recognition receptor

“…Mulla et al provide evidence that TLR10, which is expressed on trophoblast during gestation, induces apoptosis through activation of caspase-3 (7). Mulla et al also found the trigger for this response to be a TLR2 ligand (i.e., peptidoglycan); no effect on IL-6 production was found in these studies (7). Very recently, a study described that TLR10 acts as a proinflammatory TLR, which is the opposite of the suppressive function of TLR10 we report here (19 PBMCs from individuals without polymorphisms (wt; wild-type; white bars), individuals with the I369L SNP (D) or I775V SNP (E) in one of both alleles (he; heterozygous; gray bars), and individuals with the SNP in both alleles (ho; homozygous; black bars), were stimulated for 24 h at 37°C with RPMI, or B. burgdorferi.…”

“…TLR10 is predominantly expressed in tissues rich in immune cells, such as spleen, lymph node, thymus, tonsil, and lung (2). Expression of TLR10 can be induced in B cells, dendritic cells, eosinophils, and neutrophils (3,5,6), as well as on nonimmune cells, such as trophoblasts (7). TLR1 and TLR6 are known to form heterodimers with TLR2, and this was shown for TLR10 as well (3,8).…”

Functional Toll-like receptors in primary first trimester trophoblasts

“…Detection of TLR2, TLR4 and TLR10 mRNA is supported (Abrahams et al, 2004, Mulla et al, 2013), but has not previously been collectively addressed, which is required to fully understand the functionality of these receptors. The gene expression findings indicate a potential for diverse TLR signaling in primary trophoblasts, and are supported functionally by cell surface TLR2/1, TLR4 and TLR5…”

“…and TLR10 expression have been demonstrated in primary first trimester trophoblasts (Abrahams et al, 2004, Mulla et al, 2013 and of the endosomal TLRs, only TLR3 and TLR8 transcripts have been detected in early gestational placentas (Abrahams et al, 2005, Aldo et al, 2010.…”

“…Functional TLR studies related to first trimester have largely been conducted on trophoblast cell lines (Abrahams et al, 2004, Klaffenbach et al, 2005, Mulla et al, 2013, Komine-Aizawa et al, 2008, Nakada et al, 2009, Chatterjee et al, 2012, and in primary first trimester trophoblasts, TLR3 and TLR4 activated release of the pro-inflammatory cytokines IL-6, IL-8 and IFN-β has been reported (Abrahams et al, 2005, Anton et al, 2012, Wang et al, 2011. Collectively, these findings indicate that TLR-mediated trophoblast activation is of importance in pregnancy, but the knowledge is limited and the functional role of TLRs in early gestational trophoblasts has yet to be established.…”