Macrophages regulate corpus luteum development during embryo implantation in mice
Alison S. Care, … , Wendy V. Ingman, Sarah A. Robertson
Alison S. Care, … , Wendy V. Ingman, Sarah A. Robertson
Published July 8, 2013
Citation Information: J Clin Invest. 2013;123(8):3472-3487. https://doi.org/10.1172/JCI60561.
View: Text | PDF
Research Article Reproductive biology

Macrophages regulate corpus luteum development during embryo implantation in mice

Abstract

Macrophages are prominent in the uterus and ovary at conception. Here we utilize the Cd11b-Dtr mouse model of acute macrophage depletion to define the essential role of macrophages in early pregnancy. Macrophage depletion after conception caused embryo implantation arrest associated with diminished plasma progesterone and poor uterine receptivity. Implantation failure was alleviated by administration of bone marrow–derived CD11b+F4/80+ monocytes/macrophages. In the ovaries of macrophage-depleted mice, corpora lutea were profoundly abnormal, with elevated Ptgs2, Hif1a, and other inflammation and apoptosis genes and with diminished expression of steroidogenesis genes Star, Cyp11a1, and Hsd3b1. Infertility was rescued by exogenous progesterone, which confirmed that uterine refractoriness was fully attributable to the underlying luteal defect. In normally developing corpora lutea, macrophages were intimately juxtaposed with endothelial cells and expressed the proangiogenic marker TIE2. After macrophage depletion, substantial disruption of the luteal microvascular network occurred and was associated with altered ovarian expression of genes that encode vascular endothelial growth factors. These data indicate a critical role for macrophages in supporting the extensive vascular network required for corpus luteum integrity and production of progesterone essential for establishing pregnancy. Our findings raise the prospect that disruption of macrophage-endothelial cell interactions underpinning corpus luteum development contributes to infertility in women in whom luteal insufficiency is implicated.

Authors

Alison S. Care, Kerrilyn R. Diener, Melinda J. Jasper, Hannah M. Brown, Wendy V. Ingman, Sarah A. Robertson

×

Figure 2

Macrophage depletion during the pre-implantation period causes complete infertility in Cd11b-Dtr mice.

Options: View larger image (or click on image) Download as PowerPoint
Macrophage depletion during the pre-implantation period causes complete ...
(A) At autopsy on day 7.5 pc, macrophage-depleted Cd11b-Dtr mice had no visible implantation sites (lower panels) after injection with DT (25 ng/g) on day 0.5 pc or day 3.5 pc, compared with normal implantation sites (arrows) in wild-type mice given DT (upper panels). (B) Normal implantation sites (arrows) were seen when Cd11b-Dtr mice were reconstituted with wild-type bone marrow–derived CD11b+F4/80+ monocytes (Supplemental Figure 2) prior to DT injection on day 3.5 pc (Cd11b- +DT +BM). (C) Normal implantation sites (arrows) were also seen when Cd11b-Dtr mice were injected with biologically inactive [Glu52]-DT (Gl52-DT). (D) The number of implantation sites per mouse is shown for wild-type mice (WT +DT) and macrophage-depleted Cd11b-Dtr mice (Cd11b- +DT) administered DT on day 0.5 pc. (E) The number of implantation sites per mouse is shown for wild-type mice and Cd11b-Dtr mice administered PBS, DT or [Glu52]-DT on day 3.5 pc, or DT on day 3.5 pc after reconstitution with wild-type bone marrow-derived CD11b+F4/80+ monocytes (Cd11b- +DT +BM). Data are number of implantations per mouse, with mean ± SEM superimposed. The number of mice in each group is shown in parentheses. *P < 0.01, Cd11b- +DT versus WT +DT; #P < 0.01, Cd11b- +DT +BM versus Cd11b- +DT.