CXCL12 enhances exogenous CD4+CD25+ T cell migration and prevents embryo loss in non-obese diabetic mice.
ABSTRACT To investigate the possible role of CXCL12 in the migration of regulatory T (Treg) cells.
Animal model-based study.
Pregnant non-obese diabetic (NOD) mice were compared with non-immunodeficient mice.
In vivo and in vitro CXCL12 induction.
Flow cytometric analysis and Treg cell migratory assay.
A significantly high percentage of spontaneous embryo resorption was observed in both syngeneic and allogeneic pregnant NOD mice. The percentage of embryo loss in allogeneic pregnant NOD mice was significantly decreased by treatment with Treg cells and CXCL12 injection; however, no such effect was observed in syngeneic pregnant NOD mice. In addition, the migration of Treg cells induced by CXCL12 was confirmed by both in vitro and in vivo migratory assays. CXCR4, the specific receptor for CXCL12, was expressed more intensively on Treg cells than on non-Treg CD3(+) T cells, whereas CXCL12 was dominantly expressed in cytokeratin 7(+) trophoblast cells at an early stage of gestation, and its expression reduced gradually during pregnancy.
The higher level of embryo loss in allogeneic pregnant NOD mice may be due to the lack of Treg cells. CXCL12 can cause CXCR4(+) Treg cells to migrate into the pregnant uterus and establish a beneficial microenvironment for the fetus.
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ABSTRACT: A sustained neuroinflammatory response is the hallmark of many neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, and HIV-associated neurodegeneration. A specific subset of T cells, currently recognized as FOXP3(+) CD25(+) CD4(+) regulatory T cells (Tregs), are pivotal in suppressing autoimmunity and maintaining immune homeostasis by mediating self-tolerance at the periphery as shown in autoimmune diseases and cancers. A growing body of evidence shows that Tregs are not only important for maintaining immune balance at the periphery but also contribute to self-tolerance and immune privilege in the central nervous system. In this article, we first review the current status of knowledge concerning the development and the suppressive function of Tregs. We then discuss the evidence supporting a dysfunction of Tregs in several neurodegenerative diseases. Interestingly, a dysfunction of Tregs is mainly observed in the early stages of several neurodegenerative diseases, but not in their chronic stages, pointing to a causative role of inflammation in the pathogenesis of neurodegenerative diseases. Furthermore, we provide an overview of a number of molecules, such as hormones, neuropeptides, neurotransmitters, or ion channels, that affect the dysfunction of Tregs in neurodegenerative diseases. We also emphasize the effects of the intestinal microbiome on the induction and function of Tregs and the need to study the crosstalk between the enteric nervous system and Tregs in neurodegenerative diseases. Finally, we point out the need for a systems biology approach in the analysis of the enormous complexity regulating the function of Tregs and their potential role in neurodegenerative diseases. WIREs Syst Biol Med 2012. doi: 10.1002/wsbm.1187 For further resources related to this article, please visit the WIREs website. Conflict of Interest: The authors declare that they have no conflict of interest.Wiley Interdisciplinary Reviews Systems Biology and Medicine 08/2012;
Article: The chemokine receptor CXCR4 and its ligand CXCL12 are activated during implantation and placentation in sheep.[show abstract] [hide abstract]
ABSTRACT: The progression of implantation and placentation in ruminants is complex and is regulated by interplay between sex steroids and local signaling molecules, many of which have immune function. Chemokines and their receptors are pivotal factors in implantation and vascularization of the placenta. Based on known critical roles for chemokine receptor 4 (CXCR4) during early pregnancy in other species, we hypothesized that CXCR4 and its ligand CXCL12 would increase in the endometrium and conceptus in response to implantation in ewes. The objectives of the current study were to determine if CXCL12 and CXCR4 were upregulated in: endometrium from pregnant compared to non-pregnant ewes and in, conceptuses, cotyledons, caruncles and intercaruncular tissue. Tissues were collected from sheep on Days 12, 13, 14, and 15 of either the estrous cycle or pregnancy and from pregnant ewes on Days 35 and 50. Blood samples from jugular and uterine vein were also collected on all days. Conceptuses were collected from mature ewes on Days 13, 15, 16, 17, 21 and 30 of gestation. Real time PCR was used to determine relative mRNA concentrations for CXCL12 and CXCR4 and Western blot analysis was employed to confirm protein concentration. Differences described are P < 0.05. In the endometrium, CXCR4 mRNA and protein was greater on Day 15 of pregnancy compared to the estrous cycle. CXCL12 and CXCR4 mRNA in conceptuses was greater on Days 21 and 30 compared to earlier days. CXCL12 mRNA was greater in cotyledons on Day 35 compared to Day 50. On Day 35 of gestation, CXCR4 was greater compared to Day 50 in caruncle and intercaruncular tissue. White blood cells obtained from jugular and uterine vein collection had the greatest mRNA concentration of CXCL12 on Day 35 of pregnancy. A comprehensive analysis of CXCL12 and CXCR4 expression in fetal and maternal tissues during early pregnancy is reported with noteworthy differences occurring during implantation and placentation in sheep. We interpreted these data to mean that the CXCL12/CXCR4 pathway is activated during implantation and placentation in sheep and is likely playing a role in the communication between trophoblast cells and the maternal endometrium.Reproductive Biology and Endocrinology 11/2011; 9:148. · 2.05 Impact Factor