Chemokines & Pregnancy

Establishment and maintenance of a proper maternal-fetal interface is essential for successful mammalian pregnancy. Not only must the non-pregnant uterus be transformed into a cellular and molecular environment capable of implantation and fetal survival (decidualization), but a maternally-based immune tolerance of the semi-allogenic fetus must also develop and be sustained. The trophoblast is the extraembryonic layer of cells that invade the maternal tissue and form the fetal portion of the placenta (chorion). Communication between fetal trophoblast cells and maternal immune cells dictates placental development and vasculogenesis during early pregnancy. It also establishes and maintains immune privilege throughout gestation. Recent studies identify chemokines as critical factors in this process.

Chemokines are a family of structurally-related, small, secreted proteins that render their chemoattractant effect through interaction with a subgroup of seven transmembrane domain G-protein-coupled receptors. Traditionally known to recruit immune cells to mediate inflammation, chemokines are now recognized as regulators in central nervous system development and hematopoiesis.^{1, 2} During placental development, cytotrophoblasts release CCL3/MIP-1 alpha and decidual trophoblast cells lining maternal blood vessels secrete CXCL12/SDF-1, attracting CCR5⁺ and CXCR4⁺ Natural Killer (NK) cells, respectively, from the maternal circulation.^{3, 4} In response to local environmental cues (e.g. IL-15) NK cells recruited to the decidua (dNK cells) alter their phenotypic profile by down-regulating their chemokine receptors, and losing their cytolytic activity following engagement with HLA-G, a non-classical MHC Class I molecule expressed on trophoblast cells.^{3, 5, 6} Recently, Hanna et al. proposed a positive role for dNK cells, demonstrating them to be sources of angiogenic growth factors following activation of the NK-activating receptor NKp44 by ligand-bearing cytotrophoblasts.⁷ In addition to VEGF and PlGF, dNK cells release CXCL8/IL-8 and CXCL10/IP-10. These are chemokines that direct CXCR1⁺ and CXCR3⁺ trophoblast cells, towards endovascular invasion and vascular remodeling.⁷ Thus, the mutual chemokine-mediated attraction between dNK cells and invading trophoblasts appears necessary for developing a functional maternal-fetal interface early in pregnancy.

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Figure 1. The trophoblast cell expresses numerous membrane receptors and soluble molecules that contribute to fetal immune privilege and promote placental development at the maternal-fetal interface.

The regulation of the inflammatory response by chemokines has also been implicated in miscarriage. A recent epidemiological study assessing chemokine levels in the serum of pregnant women found that elevated concentrations of CXCL5/ENA-78 and CCL5/RANTES were associated with higher risk of miscarriage.⁸ Although both of these chemokines have been localized to decidual cells, it is uncertain if these circulating levels represent a placental imbalance.

Research by Martinez de la Torre and colleagues support a detrimental consequence theory of placental chemokines by reporting a beneficial role of the D6 chemokine receptor decoy in mouse fetal survival.⁹ D6 is a silent receptor expressed on lymphatic endothelium that scavenges pro-inflammatory chemokines, thus reducing ligand availability to signaling receptors.¹⁰ Following identification of D6 expression in human and mouse placenta, these authors investigated the effect of chemokines and D6 function in fetal immune privilege by subjecting pregnant wild-type (WT) and D6^-/- mice to lipopolysaccharide (LPS) injection, an animal model of inflammation-related fetal loss. Systemic LPS injection induced an increase in both circulating and placental levels of inflammatory chemokines CCL22/MDC, CCL2/MCP-1/JE and CCL11/Eotaxin in WT mice, with exaggerated levels in D6^-/- animals. Furthermore, LPS injection increased fetal loss, with significantly higher frequency observed in D6^-/- mice relative to WT mice. Attenuation of LPS-induced fetal mortality was achieved by administering neutralizing antibodies to inflammatory cytokines. Collectively, the results support the critical role of inflammatory chemokines in pregnancy, and identifies D6's protective role in pregnancy as a scavenger receptor.⁹

Undoubtedly, future research will aim to unravel the impact of chemokines on fetal development, addressing issues such as time, location, relative concentration, and cellular environment. Such data will be critical in developing treatments for reproductive challenges, such as infertility, preeclampsia, chorioamnioitis, and miscarriage.

References

1. Tran, P.B. & R.J. Miller (2003) Nat. Rev. Neurosci. 4:444.
2. Lazarini, F. et al. (2003) Glia 42:139.
3. Hanna, J. et al. (2003) Blood 102:1569.
4. Drake, P.M. et al. (2001) J. Exp. Med. 193:1199.
5. Kanellopoulos-Langevin, C. et al. (2003) Reprod. Biol. Endocrinol. 1:121.
6. Hunt, J.S. et al. (2006) Reprod. Biol. Endocrinol. 4:S10.
7. Hanna, J. et al. (2006) Nat. Med. 12:1065.
8. Whitcomb, B.W. et al. (2007) Am. J. Epidemiol. 166:323.
9. Martinez de la Torre, Y. et al. (2007) Proc. Natl. Acad. Sci. USA 104:2319.
10. Mantovani, A. et al. (2006) Nat. Rev. Immunol. 6:907.

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