Macrophages Infiltrate the Human and Rat Decidua During Term and Preterm Labor: Evidence That Decidual Inflammation Precedes Labor1

Hamilton, Sarah; Oomomian, Yasamin; Stephen, Gillian; Shynlova, Oksana; Tower, Clare; Garrod, Ainslie; Lye, Stephen J.; Jones, Rebecca L.

doi:10.1095/biolreprod.111.095505

Cited by 245 publications

(243 citation statements)

References 33 publications

Supporting

Mentioning

214

Contrasting

Unclassified

Order By: Relevance

“…13,56 We suggest a model by which leukocyte recruitment to the uterus, as part of the initiation of labour, is achieved ( Figure 5). According to this model, (i) mechanical stretch imposed by the growing fetus at late gestation contributes to the release of multiple myometrial cytokines, which activate (ii) peripheral maternal leukocytes and (iii) endothelium (iv) to promote their adhesion to ECs which (v) facilitate the entry of peripheral leukocytes into the uterine tissues.…”

Section: Discussionmentioning

confidence: 99%

“…12 Additionally, macrophage abundance in the human decidua was higher in TL than term non-labouring samples. 13 In parallel, upregulation of pro-inflammatory cytokines mRNA expression of Interleukin-1 b (IL-1b, IL-6, C-X-C motif ligand (CXCL) 8 and C-C motif ligand (CCL) 2 was observed in the myometrium of healthy labouring women. [14][15][16][17][18] Our recent data confirmed these findings and revealed a more extensive list of up-regulated cytokine and chemokine proteins (CXCL8, CXCL1, CCL2, CCL7, IL-9, IL-18, IL-1RN, tumor necrosis factor alpha (TNFa) and granulocyte colony-stimulating factor (G-CSF)) in healthy TL human myometrial tissue samples, while also detecting a higher number of macrophage and neutrophil infiltrate.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Stretch-induced human myometrial cytokines enhance immune cell recruitment via endothelial activation

2014

Self Cite

View full text Add to dashboard Cite

Spontaneous term labour is associated with amplified inflammatory events in the myometrium including cytokine production and leukocyte infiltration; however, potential mechanisms regulating such events are not fully understood. We hypothesized that mechanical stretch of the uterine wall by the growing fetus facilitates peripheral leukocyte extravasation into the term myometrium through the release of various cytokines by uterine myocytes. Human myometrial cells (hTERT-HM) were subjected to static mechanical stretch; stretch-conditioned media was collected and analysed using 48-plex Luminex assay and ELISA. Effect of stretch-conditioned media on cell adhesion molecule expression of human uterine microvascular endothelial cells (UtMVEC-Myo) was detected by quantitative polymerase chain reaction (qPCR) and flow cytometry; functional assays testing leukocyte-endothelial interactions: adhesion of leukocytes to endothelial cells and transendothelial migration of calcein-labelled primary human neutrophils as well as migration of THP-1 monocytic cells were assessed by fluorometry. The current in vitro study demonstrated that mechanical stretch (i) directly induces secretion of multiple cytokines and chemokines by hTERT-HM cells (IL-6, CXCL8, CXCL1, migration inhibitory factor (MIF), VEGF, G-CSF, IL-12p70, bFGF and platelet-derived growth factor subunit B (PDGF-bb), P,0.05); stretch-induced cytokines (ii) enhance leukocyte adhesion to the endothelium of the surrounding uterine microvasculature by (iii) inducing the expression of endothelial cell adhesion molecules and (iv) directing the transendothelial migration of peripheral leukocytes. (vi) Chemokine-neutralizing antibodies and broad-spectrum chemokine inhibitor block leukocyte migration. Our data provide a proof of mechanical regulation for leukocyte recruitment from the uterine blood vessels to the myometrium, suggesting a putative mechanism for the leukocyte infiltrate into the uterus during labour and postpartum involution.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Stretch-induced human myometrial cytokines enhance immune cell recruitment via endothelial activation

2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…In the second trimester, other leukocyte subsets emerge, such as CD4 Th cells, regulatory T cells (Tregs), alternatively activated Mws (M2), and proangiogenic neutrophils (9)(10)(11). In late gestation, especially during the onset of labor, macrophages (Mws) and eosinophils, but not neutrophils, have been shown to infiltrate into human and murine deciduae, suggesting their critical roles in labor induction and postpartum uterine remodeling (12)(13)(14)(15). Dysfunction and improper deposition of uterine leukocytes have been implicated in pregnancy disorders such as spontaneous miscarriages, pre-eclampsia, and infection-related preterm births (16,17).…”

mentioning

confidence: 99%

Unique Roles of Infiltrating Myeloid Cells in the Murine Uterus during Early to Midpregnancy

Zhao

Kalish

Schulz

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

Leukocyte infiltration into the uterus is a characteristic feature in early to midpregnancy, but the composition and function of these leukocytes are not well understood. Using a pregnant murine model, we showed that myeloid cells and uterine NK (uNK) cells were the predominant populations in uteri during early to midgestation, whereas T and B cells were constrained. Uterine myeloid populations included cells that infiltrated from the circulation (myeloid-derived suppressor cells [MDSCs], monocyte-derived macrophages [Mφs], and dendritic cells [DCs]) or proliferated from resident precursors (resident Mφs [Re-Mφs] and DCs). CD11bhiLy6-Ghi cells, representing neutrophils in both blood and uterine MDSCs, significantly increased from embryonic days 8.5 to 9.5. To understand their putative functions, we used anti–Gr-1 Ab to deplete circulating neutrophils and uterine MDSCs. In the absence of MDSC suppression, uterine DCs, T cells, and regulatory T cells expanded. Conversely, uterine MDSCs responded to LPS-induced inflammation and transformed into CD14+-activated neutrophils, resulting in an upregulation of tolerogenic DCs. A high dose of LPS (2.5 μg/mouse) significantly increased the influx of neutrophils and production of proinflammatory cytokines, such as IL-1β and TNF-α, resulting in the reduction of Re-Mφs and uNK cells, and led to placental hemorrhages and fetal deaths. In summary, uterine MDSCs are important in early to midpregnancy by responding to the maternal immunologic milieu and protecting uNK cells and Re-Mφs via MDSC’s suppressive and anti-inflammatory functions. Upsetting this delicate immune balance by factors leading to either insufficient MDSCs or excessive neutrophil infiltration in the fetomaternal interface may contribute to pregnancy failure.

show abstract

“…16 During preterm labor, it has been previously reported that macrophage infiltration is increased in the uterus. 83 Depletion of macrophages prevented cervical remodeling and preterm delivery in lipopolysaccharide-treated mice. 84 Our study of macrophage phenotypes showed that during preterm labor induced by double hit of PGN1poly(I : C), increased the number of macrophages (F4/ 801) that were double-positive for CD11c and CD206.…”

Section: Preterm Labor and Macrophage Phenotypesmentioning

confidence: 99%

Future directions of clinical laboratory evaluation of pregnancy

et al. 2014

View full text Add to dashboard Cite

In recent years, our understanding of how the immune system interacts with the developing fetus and placenta has greatly expanded. There are many laboratories that provide tests for diagnosis of pregnancy outcome in women who have recurrent pregnancy loss (RPL) or pre-eclampsia. These tests are based on the premise that immune response to the fetus is equivalent to the adaptive immune response to a transplant. New understanding leads to the concept that the activated innate response is vital for pregnancy and this can result in more effective testing and treatment to prevent an abnormal pregnancy in the future. We describe here only three such areas for future testing: one area involves sperm and semen and factors necessary for successful fertilization; another area would determine conditions for production of growth factors necessary for implantation in the uterus; finally, the last area would be to determine conditions necessary for the vascularization of the placenta and growing fetus by activated natural killer (NK) cells (combinations of killer cell immunoglobulin-like receptor (KIR) family genes with HLA-C haplotypes) that lead to capability of secreting angiogenic growth factors. These areas are novel but understanding their role in pregnancy can lead to insight into how to maintain and treat pregnancies with complicating factors. Keywords: male factor; preterm labor; recurrent pregnancy loss; seminal plasma; sperm INTRODUCTIONWhen utilizing clinical immunological testing in recurrent pregnancy loss (RPL) or preterm delivery, it should be considered that the primary function of the immune system in pregnancy is angiogenesis and its secondary function is to function as a system to kill and remove foreign pathogens. Alterations in the immune system can affect angiogenesis or the blood flow, which is necessary to maintain placental growth and thereby may divert the immune system from its non-pregnant primary function. At present, the most commonly performed tests to monitor and treat women with RPL are tests for autoantibodies such as antiphospholipid antibodies, antinuclear antibodies and anti-thyroid antibodies.1-3 In addition, assays for lymphocyte subsets and their functions, determination of HLA histocompatibility genes and genes related to thrombophilic conditions are used by some physicians to aid in treatment. Some physicians test women to determine if their RPL are due to an inappropriate inflammatory immune response, which may be treated by anti-inflammatory drug regimens. Some of the tests that are performed have been a matter of controversy but one might consider that women with histories of RPL should be tested to determine if a reason for the repeated miscarriages can be identified. Finally, women with preterm delivery usually are tested for infections or fetal fibronectin which can be helpful in the treatment. 4 The immune system is an endocrine-like system capable of producing numerous peptide hormones (cytokines and chemokines). These hormones are key in the vascularization necessary for pla...

show abstract

Macrophages Infiltrate the Human and Rat Decidua During Term and Preterm Labor: Evidence That Decidual Inflammation Precedes Labor1

Cited by 245 publications

References 33 publications

Stretch-induced human myometrial cytokines enhance immune cell recruitment via endothelial activation

Stretch-induced human myometrial cytokines enhance immune cell recruitment via endothelial activation

Unique Roles of Infiltrating Myeloid Cells in the Murine Uterus during Early to Midpregnancy

Future directions of clinical laboratory evaluation of pregnancy

Contact Info

Product

Resources

About