title: Sphingolipid pathway regulates innate immune responses at the fetomaternal interface during pregnancy.
abstract: For a successful pregnancy, the mother's immune system has to tolerate the semiallogeneic fetus. A deleterious immune attack is avoided by orchestration of cellular, hormonal, and enzymatic factors. However, the precise mechanisms underlying fetomaternal tolerance are not yet completely understood. In this study, we demonstrate that sphingolipid metabolism constitutes a novel signaling pathway that is indispensable for fetomaternal tolerance by regulating innate immune responses at the fetomaternal interface. Perturbation of the sphingolipid pathway by disruption of the sphingosine kinase gene (Sphk) during pregnancy caused unusually high expression of neutrophil chemoattractants, CXCL1 and CXCL2, in the decidua, leading to a massive infiltration of neutrophils into the fetomaternal interface with enhanced oxidative damage, resulting in early fetal death. Sphk-deficient mice also exhibited neutrophilia in the peripheral blood, enhanced generation of granulocytes in the bone marrow, and a decrease in the number of decidual natural killer cells. The blockage of neutrophil influx protected Sphk-deficient mice against pregnancy loss. Notably, a similar result was obtained in human decidual cells, in which Sphk deficiency dramatically increased the secretion of CXCL1 and IL-8. In conclusion, our findings suggest that the sphingolipid metabolic pathway plays a critical role in fetomaternal tolerance by regulating innate immunity at the fetomaternal interface both in mice and humans, and it could provide novel insight into the development of therapeutic strategies to treat idiopathic pregnancy loss in humans.
authors.affiliation: From the Department of Hematology and Oncology, Kyoto University Hospital, Kyoto 606-8507, Japan, the Department of Pharmacotherapy, Research Institute of Pharmaceutical Sciences, Musashino University, Nishitokyo, Tokyo 202-8585, Japan, kiyomim@kuhp.kyoto-u.ac.jp.
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Mizugishi
authors.affiliation: the Department of Gynecology and Obstetrics, Adachi Hospital, Kyoto 604-0837, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Inoue
authors.affiliation: the Department of Gynecology and Obstetrics, Adachi Hospital, Kyoto 604-0837, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hatayama
authors.affiliation: the Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, and.
authors.forename: Jacek
authors.initials: J
authors.lastname: Bielawski
authors.affiliation: the Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, and.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Pierce
authors.affiliation: the Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Yukiyasu
authors.initials: Y
authors.lastname: Sato
authors.affiliation: From the Department of Hematology and Oncology, Kyoto University Hospital, Kyoto 606-8507, Japan.
authors.forename: Akifumi
authors.initials: A
authors.lastname: Takaori-Kondo
authors.affiliation: the Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Konishi
authors.affiliation: From the Department of Hematology and Oncology, Kyoto University Hospital, Kyoto 606-8507, Japan.
authors.forename: Kouhei
authors.initials: K
authors.lastname: Yamashita
mesh_terms: D000022:Abortion, Spontaneous / Q000235:genetics; D000818:Animals; D054360:Chemokine CXCL1 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D003656:Decidua / Q000166:cytology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007108:Immune Tolerance; D007113:Immunity, Innate; D016209:Interleukin-8 / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics* / Q000378:metabolism; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000276:immunology*; D013107:Sphingolipids / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology; D013997:Time Factors; D000099157:Sphingosine Kinase
chemical_list: D054360:Chemokine CXCL1; D018925:Chemokines; D016209:Interleukin-8; D017853:Phosphotransferases (Alcohol Group Acceptor); D013107:Sphingolipids; D000099157:Sphingosine Kinase; C475895:Cxcl1 protein, mouse
keywords: Chemokine; Decidual Cell; Fetomaternal Tolerance; Innate Immunity; Neutrophil; Pregnancy; Sphingolipid; Sphingosine Kinase