VIP contribution to the decidualization program: regulatory T cell recruitment

Abstract

During early pregnancy, the human uterus undergoes profound tissue remodeling characterized by leukocyte invasion and production of proinflammatory cytokines, followed by tissue repair and tolerance maintenance induction. Vasoactive intestinal peptide (VIP) is produced by trophoblast cells and modulates the maternal immune response toward a tolerogenic profile. Here, we evaluated the contribution of the VIP/VPAC to endometrial renewal, inducing decidualization and the recruitment of induced regulatory T cells (iTregs) that accompany the implantation period. For that purpose, we used an in vitro model of decidualization with a human endometrial stromal cell line (HESC) stimulated with progesterone (P 4 ) and lipopolysaccharide (LPS) simulating the inflammatory response during implantation and human iTregs (CD4) differentiated from naïve T cells obtained from peripheral blood mononuclear cells of fertile women. We observed that VIP and its receptor VPAC1 are constitutively expressed in HESCs and that P 4 increased VIP expression. Moreover, in HESC VIP induced expression of RANTES (CCL5), one of the main chemokines involved in T cell recruitment, and this effect is enhanced by the presence of P 4 and LPS. Finally, assays of the migration of iTregs toward conditioned media from HESCs revealed that endogenous VIP production induced by P 4 and LPS and RANTES production were involved, as anti-RANTES neutralizing Ab or VIP antagonist prevented their migration. We conclude that VIP may have an active role in the decidualization process, thus contributing to recruitment of iTregs toward endometrial stromal cells by increasing RANTES expression in a P 4 -dependent manner.

Current concepts in maternal-fetal immunology: Recognition and response to microbial pathogens by decidual stromal cells

“…, those involved in prostaglandin production) [32], and decreased solute carrier family 40 member 1 (SLC40A1), which is key in modulating iron levels [32]. Utilizing an immortalized line of human decidualized endometrial stromal cells, Grasso and colleagues assessed responses to LPS, which also elicited increased gene expression of regulated on activation, normal T cell expressed and secreted (RANTES), MCP-1 and IL-8 [34]. …”

“…Other studies utilizing primary human DSCs observed increased gene expression of TNFα, 32,33 IL-6, 17,32,33 lipid metabolism genes (eg, those involved in prostaglandin production),32 and decreased solute carrier family 40 member 1 (SLC40A1), which is key in modulating iron levels 32. Utilizing an immortalized line of human decidualized endometrial stromal cells, Grasso and colleagues assessed responses to LPS, which also elicited the increased gene expression of regulated on activation, normal T cell expressed and secreted (RANTES), MCP-1, and IL-8 34. At the protein level, MCP-1 production by primary human DSCs was increased after LPS stimulation, which may be important in recruitment of monocytes to areas of inflammation 20,35.…”

M1/M2 Macrophage Polarity in Normal and Complicated Pregnancy

“…Other phenotypic features that suggest these cells are pro-M2 include constitutive expression of DC-sign (CD209), high levels of CD163, CD68, CD45, hyaluronan receptor LYVE-1, and HLA antigens A, B, and C, IL-10, and TGF-β (37–39). Hofbauer cells may have a role in placental angiogenesis, remodeling of the extracellular matrix, and modulation of inflammation, which are M2 characteristics (39–41). Although not a particular feature of macrophage function, it has been suggested that Hofbauer cells participate in the regulation of stromal fluid balance, ion exchange, and transfer of serum proteins to the vascular system (36).…”

“…The physical changes that occur during decidualization include proliferation of luminal epithelium, development of secretory glandules with large apical protrusions (pinopodes) and microvilli, and transformation of fibroblast-like endometrial stromal cells into larger rounded cells (47, 48). In addition, endometrial cells produce a variety of compounds that attract leukocytes to the decidualized tissue such as prolactin, colony stimulating factor 1 (CSF-1), macrophage inhibitory factor (MIF), IL-15, insulin growth factor binding protein-1 (IGFBP-1), and cyclooxygenase-2 (COX-2), and cell adhesion molecules (ICAM-1, VACM-1, LFA-3, H-CAM) (41, 45, 48, 49). Both CSF-1and MIF influence the recruitment of macrophages into the decidua (11, 43, 50, 51).…”

“…This, in part, is caused by the uneven spatial distribution of neighboring leukocytes and trophoblasts within the decidua, which provide different cues to resident macrophages. Events that account for these changes include the contribution of immunoregulatory molecules from trophoblasts such as HLA-G (68, 69), TGF-β (40), and VIP (41). These compounds have direct effects on macrophages or on Tregs, which express pro-M2 factors such as IDO and IL-10 (1).…”