Innate Lymphoid Cells in the Maternal and Fetal Compartments

Pregnancy success is orchestrated by the complex balance between the maternal and fetal immune systems. Herein, we summarize the potential role of innate lymphoid cells (ILCs) in the maternal and fetal compartments. We reviewed published literature describing different ILC subsets [ILC1s, ILC2s, ILC3s, and lymphoid tissue inducer (LTi) cells] in the uterus, decidua, fetal tissues [liver, secondary lymphoid organs (SLO), intestine, and lung] and amniotic cavity. ILC1s, ILC2s, and ILC3s are present in the murine uterus prior to and during pregnancy but have only been detected in the non-pregnant endometrium in humans. Specifically, ILC2s reside in the murine uterus from mid-pregnancy to term, ILC1s increase throughout gestation, and ILC3s remain constant. Yet, LTi cells have only been detected in the non-pregnant murine uterus. In the human decidua, ILC1s, ILC3s, and LTi-like cells are more abundant during early gestation, whereas ILC2s increase at the end of pregnancy. Decidual ILC1s were also detected during mid-gestation in mice. Interestingly, functional decidual ILC2s and ILC3s increased in women who underwent spontaneous preterm labor, indicating the involvement of such cells in this pregnancy complication. Fetal ILCs exist in the liver, SLO, intestine, lung, and amniotic cavity. The fetal liver is thought to be the source of ILC progenitors since the differentiation of these cells from hematopoietic stem cells occurs at this site, and mature ILC subsets can be found in this compartment as well. The interaction between LTi cells and specialized stromal cells is important during the formation of SLO. Mature ILCs are found at the mucosal surfaces of the lung and intestine, from where they can extravasate into the amniotic cavity. Amniotic fluid ILCs express high levels of RORγt, CD161, and CD103, hallmarks of ILC3s. Such cells are more abundant in the second trimester than later in gestation. Although amniotic fluid ILC3s produce IL-17A and TNFα, indicating their functionality, their numbers in patients with intra-amniotic infection/inflammation remain unchanged compared to those without this pregnancy complication. Collectively, these findings suggest that maternal (uterine and decidual) ILCs play central roles in both the initiation and maintenance of pregnancy, and fetal ILCs participate in the development of immunity

Maternal circulating leukocytes display early chemotactic responsiveness during late gestation

Abstract Background Parturition has been widely described as an immunological response; however, it is unknown how this is triggered. We hypothesized that an early event in parturition is an increased responsiveness of peripheral leukocytes to chemotactic stimuli expressed by reproductive tissues, and this precedes expression of tissue chemotactic activity, uterine activation and the systemic progesterone/estradiol shift. Methods Tissues and blood were collected from pregnant Long-Evans rats on gestational days (GD) 17, 20 and 22 (term gestation). We employed a validated Boyden chamber assay, flow cytometry, quantitative real time-polymerase chain reaction, and enzyme-linked immunosorbent assays. Results We found that GD20 maternal peripheral leukocytes migrated more than those from GD17 when these were tested with GD22 uterus and cervix extracts. Leukocytes on GD20 also displayed a significant increase in chemokine (C-C motif) ligand 2 (Ccl2) gene expression and this correlated with an increase in peripheral granulocyte proportions and a decrease in B cell and monocyte proportions. Tissue chemotactic activity and specific chemokines (CCL2, chemokine (C-X-C motif) ligand 1/CXCL1, and CXCL10) were mostly unchanged from GD17 to GD20 and increased only on GD22. CXCL10 peaked on GD20 in cervical tissues. As expected, prostaglandin F2α receptor and oxytocin receptor gene expression increased dramatically between GD20 and 22. Progesterone concentrations fell and estradiol-17β concentrations increased in peripheral serum, cervical and uterine tissue extracts between GD20 and 22. Conclusion Maternal circulating leukocytes display early chemotactic responsiveness, which leads to their infiltration into the uterus where they may participate in the process of parturition

CD71+ erythroid cells from neonates born to women with preterm labor regulate cytokine and cellular responses

Neonatal CD71+ erythroid cells are thought to have immunosuppressive functions. Recently, we demonstrated that CD71+ erythroid cells from neonates born to women who underwent spontaneous preterm labor (PTL) are reduced to levels similar to those of term neonates; yet, their functional properties are unknown. Herein, we investigated the functionality of CD71+ erythroid cells from neonates born to women who underwent spontaneous preterm or term labor. CD71+ erythroid cells from neonates born to women who underwent PTL displayed a similar mRNA profile to that of those from term neonates. The direct contact between preterm or term neonatal CD71+ erythroid cells and maternal mononuclear immune cells, but not soluble products from these cells, induced the release of proinflammatory cytokines and a reduction in the release of TGFâ β. Moreover, PTLâ derived neonatal CD71+ erythroid cells (1) modestly altered CD8+ T cell activation; (2) inhibited conventional CD4+ and CD8+ Tâ cell expansion; (3) suppressed the expansion of CD8+ regulatory T cells; (4) regulated cytokine responses mounted by myeloid cells in the presence of a microbial product; and (5) indirectly modulated Tâ cell cytokine responses. In conclusion, neonatal CD71+ erythroid cells regulate neonatal Tâ cell and myeloid responses and their direct contact with maternal mononuclear cells induces a proinflammatory response. These findings provide insight into the biology of neonatal CD71+ erythroid cells during the physiologic and pathologic processes of labor.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142950/1/jlb10051_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142950/2/jlb10051-sup-0003-TableS2.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142950/3/jlb10051-sup-0002-TableS1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142950/4/jlb10051-sup-0001-Figures.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142950/5/jlb10051.pd

Amniotic fluid neutrophils can phagocytize bacteria: A mechanism for microbial killing in the amniotic cavity

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138926/1/aji12723_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138926/2/aji12723.pd

Intra‐Amniotic Administration of HMGB1 Induces Spontaneous Preterm Labor and Birth

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/116331/1/aji12443_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/116331/2/aji12443.pd

The amniotic fluid cell-free transcriptome in spontaneous preterm labor

The amniotic fluid (AF) cell-free RNA was shown to reflect physiological and pathological processes in pregnancy, but its value in the prediction of spontaneous preterm delivery is unknown. Herein we profiled cell-free RNA in AF samples collected from women who underwent transabdominal amniocentesis after an episode of spontaneous preterm labor and subsequently delivered within 24 h (n = 10) or later (n = 28) in gestation. Expression of known placental single-cell RNA-Seq signatures was quantified in AF cell-free RNA and compared between the groups. Random forest models were applied to predict time-to-delivery after amniocentesis. There were 2385 genes differentially expressed in AF samples of women who delivered within 24 h of amniocentesis compared to gestational age-matched samples from women who delivered after 24 h of amniocentesis. Genes with cell-free RNA changes were associated with immune and inflammatory processes related to the onset of labor, and the expression of placental single-cell RNA-Seq signatures of immune cells was increased with imminent delivery. AF transcriptomic prediction models captured these effects and predicted delivery within 24 h of amniocentesis (AUROC = 0.81). These results may inform the development of biomarkers for spontaneous preterm birth

Are B cells altered in the decidua of women with preterm or term labor?

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149277/1/aji13102_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149277/2/aji13102.pd

Inflammation-Induced Adverse Pregnancy and Neonatal Outcomes Can Be Improved by the Immunomodulatory Peptide Exendin-4

Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. Inflammation is causally linked to preterm birth; therefore, finding an intervention that dampens maternal and fetal inflammatory responses may provide a new strategy to prevent adverse pregnancy and neonatal outcomes. Using animal models of systemic maternal inflammation [intraperitoneal injection of lipopolysaccharide (LPS)] and fetal inflammation (intra-amniotic administration of LPS), we found that (1) systemic inflammation induced adverse pregnancy and neonatal outcomes by causing a severe maternal cytokine storm and a mild fetal cytokine response; (2) fetal inflammation induced adverse pregnancy and neonatal outcomes by causing a mild maternal cytokine response and a severe fetal cytokine storm; (3) exendin-4 (Ex4) treatment of dams with systemic inflammation or fetal inflammation improved adverse pregnancy outcomes by modestly reducing the rate of preterm birth; (4) Ex4 treatment of dams with systemic, but not local, inflammation considerably improved neonatal outcomes, and such neonates continued to thrive; (5) systemic inflammation facilitated the diffusion of Ex4 through the uterus and the maternal–fetal interface; (6) neonates born to Ex4-treated dams with systemic inflammation displayed a similar cytokine profile to healthy control neonates; and (7) treatment with Ex4 had immunomodulatory effects by inducing an M2 macrophage polarization and increasing anti-inflammatory neutrophils, as well as suppressing the expansion of CD8+ regulatory T cells, in neonates born to dams with systemic inflammation. Collectively, these results provide evidence that dampening maternal systemic inflammation through novel interventions, such as Ex4, can improve the quality of life for neonates born to women with this clinical condition

RNA Sequencing Reveals Diverse Functions of Amniotic Fluid Neutrophils and Monocytes/Macrophages in Intra-Amniotic Infection

Intra-amniotic infection, the invasion of microbes into the amniotic cavity resulting in inflammation, is a clinical condition that can lead to adverse pregnancy outcomes for the mother and fetus as well as severe long-term neonatal morbidities. Despite much research focused on the consequences of intra-amniotic infection, there remains little knowledge about the innate immune cells that respond to invading microbes. We performed RNA-seq of sorted amniotic fluid neutrophils and monocytes/macrophages from women with intra-amniotic infection to determine the transcriptomic differences between these innate immune cells. Further, we sought to identify specific transcriptomic pathways that were significantly altered by the maternal or fetal origin of amniotic fluid neutrophils and monocytes/macrophages, the presence of a severe fetal inflammatory response, and pregnancy outcome (i.e., preterm or term delivery). We show that significant transcriptomic differences exist between amniotic fluid neutrophils and monocytes/macrophages from women with intra-amniotic infection, indicating the distinct roles these cells play. The transcriptome of amniotic fluid immune cells varies based on their maternal or fetal origin, and the significant transcriptomic differences between fetal and maternal monocytes/macrophages imply that those of fetal origin exhibit impaired functions. Notably, transcriptomic changes in amniotic fluid monocytes/macrophages suggest that these immune cells collaborate with neutrophils in the trafficking of fetal leukocytes throughout the umbilical cord (i.e., funisitis). Finally, amniotic fluid neutrophils and monocytes/macrophages from preterm deliveries display enhanced transcriptional activity compared to those from term deliveries, highlighting the protective role of these cells during this vulnerable period. Collectively, these findings demonstrate the underlying complexity of local innate immune responses in women with intra-amniotic infection and provide new insights into the functions of neutrophils and monocytes/macrophages in the amniotic cavity. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements