title: Unique roles of infiltrating myeloid cells in the murine uterus during early to midpregnancy.
abstract: 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). CD11b(hi)Ly6-G(hi) 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.
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305; and huizhao2@stanford.edu.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305; and.
authors.forename: Flora
authors.initials: F
authors.lastname: Kalish
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305; and.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schulz
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305; and.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Wong
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305; and.
authors.forename: David K
authors.initials: DK
authors.lastname: Stevenson
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000276:immunology*; D049109:Cell Proliferation; D005260:Female; D005313:Fetal Death; D053583:Interleukin-1beta / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology; D018950:Lipopolysaccharide Receptors / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D022423:Myeloid Cells / Q000276:immunology* / Q000473:pathology; D020556:Neutrophil Infiltration / Q000276:immunology; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D011247:Pregnancy; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D014592:Uterine Hemorrhage / Q000276:immunology / Q000473:pathology; D014599:Uterus / Q000276:immunology* / Q000473:pathology
chemical_list: C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D018950:Lipopolysaccharide Receptors; D014409:Tumor Necrosis Factor-alpha