title: Infiltration of myeloid cells in the pregnant uterus is affected by heme oxygenase-1.
abstract: Infiltrating myeloid cells in pregnant uteri play critical roles in the establishment of the placenta and maintenance of normal pregnancies. Their recruitment and proliferation are primarily mediated by the interactions of cytokines and chemokines secreted locally with their corresponding receptors. Heme oxygenase-1 (HO-1) has various physiologic properties that contribute to placental vascular development, with deficiencies in HO-1 associated with pregnancy disorders. Here, we investigated the effect of HO-1 on myeloid cell infiltration into pregnant uteri using a partial HO-1-deficient (Het, HO-1+/-) mouse model. With the use of flow cytometry, HO-1 was found predominantly expressed in circulating and uterine myeloid cells, specifically neutrophils and monocytes/macrophages. In pregnant Het uteri, the numbers of neutrophils and monocytes/macrophages were significantly reduced compared with pregnant wild-type (WT; HO-1+/+) uteri. With the use of BrdU in vivo assays, HO-1 deficiency did not affect cell proliferation or blood cell populations. With the use of PCR arrays, gene expression of cytokines (Csf1, Csf3), chemokines (Ccl1, Ccl2, Ccl6, Ccl8, Ccl11, Ccl12, Cxcl4, Cxcl9, Cxcl12), and their receptors (Ccr1, Ccr2, Ccr3, Ccr5) were also reduced significantly in Het compared with pregnant WT uteri. Moreover, with the use of flow cytometry, myeloid CSF1R and CCR2 expression in blood and uteri from both pregnant and nonpregnant mice was characterized, and a deficiency in HO-1 significantly reduced CCR2 expression in infiltrating uterine monocytes/macrophages and dendritic cells (DCs). These data reveal that HO-1 regulates not only cytokine/chemokine production in pregnant uteri but also myeloid cell receptor numbers, suggesting a role of HO-1 in the recruitment and maintenance of myeloid cells in pregnant uteri and subsequent effects on placental vascular formation.
authors.affiliation: Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Stanford, California, USA huizhao2@stanford.edu.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Flora
authors.initials: F
authors.lastname: Kalish
authors.affiliation: Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Wong
authors.affiliation: Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: David K
authors.initials: DK
authors.lastname: Stevenson
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D001854:Bone Marrow Cells / Q000473:pathology; D001973:Bromodeoxyuridine / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D018925:Chemokines / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006579:Heterozygote; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000201:enzymology* / Q000473:pathology*; D011247:Pregnancy; D054390:Receptors, CCR2 / Q000378:metabolism; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D014599:Uterus / Q000201:enzymology* / Q000473:pathology*
chemical_list: D000950:Antigens, Ly; D018925:Chemokines; C000604004:Csf1r protein, mouse; C494192:Ly-6C antigen, mouse; D054390:Receptors, CCR2; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D051547:Heme Oxygenase-1; D001973:Bromodeoxyuridine
keywords: cell recruitment/emigration; chemokines; chemotaxis; cytokines; placenta