The immunology of pregnancy is complex and poorly defined. During the complex process of pregnancy, macrophages secrete many cytokines/chemokines and play pivotal roles in the maintenance of maternal-fetal tolerance. Here, we summarized the current knowledge of macrophage polarization and the mechanisms involved in physiological or pathological pregnancy processes, including miscarriage, preeclampsia, and preterm birth. Although current evidence provides a compelling argument that macrophages are important in pregnancy, our understanding of the roles and mechanisms of macrophages in pregnancy is still rudimentary. Since macrophages exhibit functional plasticity, they may be ideal targets for therapeutic manipulation during pathological pregnancy. Additional studies are needed to better define the functions and mechanisms of various macrophage subsets in both normal and pathological pregnancy.

/pdf/macrophage-polarization-in-physiological-and-pathological-1dye7urftw.pdf

Macrophage Polarization in Physiological and Pathological Pregnancy.

A successful pregnancy requires a fine-tuned and highly regulated balance between immune activation and embryonic antigen tolerance. Since the fetus is semi-allogeneic, the maternal immune system should exert tolerant to the fetus while maintaining the defense against infection. The maternal-fetal interface consists of different immune cells, such as decidual natural killer (dNK) cells, macrophages, T cells, dendritic cells, B cells, and NKT cells. The interaction between immune cells, decidual stromal cells, and trophoblasts constitute a vast network of cellular connections. A cellular immunological imbalance may lead to adverse pregnancy outcomes, such as recurrent spontaneous abortion, pre-eclampsia, pre-term birth, intrauterine growth restriction, and infection. Dynamic changes in immune cells at the maternal-fetal interface have not been clearly stated. While many studies have described changes in the proportions of immune cells in the normal maternal-fetus interface during early pregnancy, few studies have assessed the immune cell changes in mid and late pregnancy. Research on pathological pregnancy has provided clues about these dynamic changes, but a deeper understanding of these changes is necessary. This review summarizes information from previous studies, which may lay the foundation for the diagnosis of pathological pregnancy and put forward new ideas for future studies.

/pdf/dynamic-function-and-composition-changes-of-immune-cells-285pzpa2w0.pdf

Dynamic Function and Composition Changes of Immune Cells During Normal and Pathological Pregnancy at the Maternal-Fetal Interface.

Mesenchymal stem cell-derived magnetic extracellular nanovesicles for targeting and treatment of ischemic stroke

Macrophages (MФs) are the leukocytes produced from differentiation of monocytes and are located in almost all tissues of human body. They are involved in various processes, such as phagocytosis, innate and adaptive immunity, proinflammatory (M1) and anti-inflammatory (M2) activity, depending on the tissue microenvironment. They play a crucial role in pregnancy, and their dysfunction or alteration of polarity is involved in pregnancy disorders, like preeclampsia, recurrent spontaneous abortion, infertility, intrauterine growth restriction, and preterm labor. About 50-60% of decidual leukocytes are natural killer (NK) cells followed by MФs (the second largest population). MФs are actively involved in trophoblast invasion, tissue and vascular remodeling during early pregnancy, besides their role as major antigen-presenting cells in the decidua. These cells have different phenotypes and polarities in different stages of pregnancy. They have also been observed to enhance tumor growth by their anti-inflammatory activity (M2 type) and prevent immunogenic rejection. Targeted alteration of polarity (M1-M2 or vice versa) could be a major focus in the future treatment of pregnancy complications. This review is focused on the role of MФs in pregnancy, their involvement in pregnancy disorders, and decidual MФs as possible therapeutic targets for the treatment of pregnancy complications.

/pdf/role-of-macrophages-in-pregnancy-and-related-complications-1jj4p66xuu.pdf

Role of Macrophages in Pregnancy and Related Complications.

Background Diffuse intrinsic pontine glioma (DIPG) is a uniformly fatal CNS tumor diagnosed in 300 American children per year Radiation is the only effective treatment and extends overall survival to a median of 11 months Due to its location in the brainstem, DIPG cannot be surgically resected Immunotherapy has the ability to target tumor cells specifically; however, little is known about the tumor microenvironment in DIPGs We sought to characterize infiltrating immune cells and immunosuppressive factor expression in pediatric low- and high-grade gliomas and DIPG Methods Tumor microarrays were stained for infiltrating immune cells RNA was isolated from snap-frozen tumor tissue and Nanostring analysis performed DIPG and glioblastoma cells were co-cultured with healthy donor macrophages, T cells, or natural killer (NK) cells, and flow cytometry and cytotoxicity assays performed to characterize the phenotype and function, respectively, of the immune cells Results DIPG tumors do not have increased macrophage or T-cell infiltration relative to nontumor control, nor do they overexpress immunosuppressive factors such as programmed death ligand 1 and/or transforming growth factor β1 H33-K27M DIPG cells do not repolarize macrophages, but are not effectively targeted by activated allogeneic T cells NK cells lysed all DIPG cultures Conclusions DIPG tumors have neither a highly immunosuppressive nor inflammatory microenvironment Therefore, major considerations for the development of immunotherapy will be the recruitment, activation, and retention of tumor-specific effector immune cells

/pdf/characterization-of-the-immune-microenvironment-of-diffuse-2cq4leyoi7.pdf

Characterization of the immune microenvironment of diffuse intrinsic pontine glioma: implications for development of immunotherapy.

It is increasingly evident that cytokines and growth factors produced in the decidua play a pivotal role in the regulation of the local immune microenvironment and the establishment of pregnancy. One of the major growth factors produced in the decidua is vascular endothelial growth factor (VEGF), which acts not only on endothelial cells, but also on multiple other cell types, including macrophages. We sought to determine whether decidua-derived VEGF affects macrophage recruitment and polarization using human endometrial/decidual tissue samples, primary human endometrial stromal cells (ESCs), and the human monocyte cell line THP1. In situ hybridization was used for assessment of local VEGF expression and immunohistochemistry was used for identification and localization of CD68-positive endometrial macrophages. Macrophage migration in culture was assessed using a transwell migration assay, and the various M1/M2 phenotypic markers and VEGF expression were assessed using quantitative real-time PCR (qRT-PCR). We found dramatic increases in both VEGF levels and macrophage numbers in the decidua during early pregnancy compared to the secretory phase endometrium (non-pregnant), with a significant increase in M2 macrophage markers, suggesting that M2 is the predominant macrophage phenotype in the decidua. However, decidual samples from preeclamptic pregnancies showed a significant shift in macrophage phenotype markers, with upregulation of M1 and downregulation of M2 markers. In THP1 cultures, VEGF treatment significantly enhanced macrophage migration and induced M1 macrophages to shift to an M2 phenotype. Moreover, treatment with conditioned media from decidualized ESCs induced changes in macrophage migration and polarization similar to that of VEGF treatment. These effects were abrogated by the addition of a potent VEGF inhibitor. Together these results suggest that decidual VEGF plays a significant role in macrophage recruitment and M2 polarization, and that inhibition of VEGF signaling may contribute to the shift in macrophage polarity observed in different pregnancy disorders, including preeclampsia.

/pdf/vegf-may-contribute-to-macrophage-recruitment-and-m2-k7re0uttxj.pdf

VEGF may contribute to macrophage recruitment and M2 polarization in the decidua

The purpose of the study is to determine whether continued stimulation of mature follicles to allow “catch up” growth of medium-sized follicles in assisted reproductive technology compromises the clinical pregnancy (CPR) and live birth (LBR) rates in IVF/ICSI cycles. This retrospective cohort study reviewed 200 first IVF ± ICSI cycles out of a total of 340 cycles with complete data. Women underwent stimulation protocols with gonadotropins (Gn) and GnRH antagonist. Treatment cycles were divided into two groups (Gp): hCG administration delayed despite the presence of two mature follicles, defined as ≥ 18 mm [Gp1, n = 79] and hCG administration given when there were two mature follicles [Gp2, n = 121]. The patients in Gp1 were significantly younger than those in Gp2 [32.9 (4.5) vs. 34.3 (4.8), p = 0.04] and needed a median of one more day of superovulation before ovulation was triggered with hCG. The extra days was associated with the use of 450 [75–2025] more Gn, such that at the time the hCG was administered, patient’s in group 1 had developed significantly greater number of follicles ≥ 18 mm [mean (SD), 4.9 (1.8) vs. 3.4 (1.7), p < 0.0001]. The clinical pregnancy (48.1 vs. 38.0%, [OR (95% CI)] [1.6 (1.0–2.5), p = 0.09]) and live birth (43.0 vs. 35.5%, [1.4 (0.9–2.3), p = 0.21]) rates per cycle started were not significantly different between the two groups. Forward stepwise logistic regression showed that only maternal age (p = 0.04) influenced clinical pregnancy rates (OR = 0.88, CI 0.78–0.99) and only the number of days for superovulation influenced live birth rates (OR = 0.65, CI 0.486–0.869). This study demonstrated that delaying hCG administration to allow further growth of the medium-sized follicles added further days of superovulation and cost without improvement in CPR and LBR.

/pdf/the-value-of-delaying-hcg-administration-to-enable-2625v09lct.pdf

Karen Wheeler

Papers

VEGF may contribute to macrophage recruitment and M2 polarization in the decidua

The value of delaying hCG administration to enable maturation of medium-sized follicles in patients undergoing superovulation for IVF/ICSI.