Macrophages: important accessory cells for reproductive function

Abstract

Macrophages are found throughout reproductive tissues. To determine their role(s), we have studied mice homozygous for a null mutation (Csfm(op)) in the gene encoding the major macrophage growth factor, colony-stimulating factor-1 (CSF-1). Both male and female Csfm(op)/Csfm(op) mice have fertility defects. Males have low sperm number and libido as a consequence of dramatically reduced circulating testosterone. Females have extended estrous cycles and poor ovulation rates. CSF-1 is the principal growth factor regulating macrophage populations in the testis, male accessory glands, ovary, and uterus. However, analyses of CSF-1 nullizygous mice suggest that the primary reproductive defect is in the development of feedback regulation of the hypothalamic-pituitary axis. Although not correlating with deficiencies of microglia populations, electrophysiological investigations indicate an impairment of neuronal responses. This suggests that microglia, under the influence of CSF-1, act to organize neuronal connectivity during development and that the absence of this function results in a perturbation of the hypothalamic-pituitary-gonadal axis. Macrophages also appear to have functions in the differentiated tissues of the reproductive system, including having a positive influence on steroidogenic cells. These data suggest that macrophages, through their trophic functions, can be considered as essential accessory cells for normal reproductive functioning.

Incomplete restoration of colony-stimulating factor 1 (CSF-1) function in CSF-1–deficient Csf1op/Csf1op mice by transgenic expression of cell surface CSF-1

“…The important role of CSF-1 in ovulation, preimplantation, placental function, regulation of the estrous cycle, and lactation has been described previously (for reviews, see Pollard and Stanley 5 and Cohen et al 6 ). Both the CSF-1-deficient Csf1 op /Csf1 op mice and the CSF-1R-null mice have increased estrous cycle times, a failure of mammary gland development during pregnancy, and a decreased male libido.…”

“…5,6,51 Despite their powdered chow and milk formula diet, these mice still exhibit a decreased adult body weight and a markedly retarded growth rate ( Figure 2A). We previously showed that the full-length transgene, TgC, is able to fully restore the growth retardation in Csf1 op /Csf1 op ; TgC/ϩ mice.…”

“…[1][2][3][4][5][6] All effects of CSF-1 are mediated by a high-affinity receptor tyrosine kinase 7-10 encoded by the c-fms proto-oncogene. 11 At least 5 mature human or mouse CSF-1 mRNAs (4.0 kb, 3.0 kb, 2.3 kb, 1.9 kb, and 1.6 kb) resulting from alternative splicing in exon 6 and the alternative usages of the 3Ј-untranslated region exons 9 and 10, [12][13][14][15][16][17][18] have been shown to encode 3 isoforms of the CSF-1 protein: a secreted glycoprotein, 19-21 a secreted proteoglycan, 22,23 and a biologically active membrane-spanning cell surface glycoprotein 18,[24][25][26][27][28][29] (for a review, see Stanley 30 ).…”

Macrophages and CSF-1

“…Csf1 op/op mice are severely depleted in ovarian, uterine and placental macrophages. 128 Macrophages are important accessory cells in reproduction and it is the absence of CSF-1-mediated tissue macrophage regulation that is responsible for the primary fertility defects observed in Csf1 op/op mice.…”

Origins and functions of phagocytes in the embryo

“…Also unaffected in op/op mice are dendritic cells and Langerhans cells. In addition to macrophage and osteoclast deficiencies, the animals have developmental defects of the nervous and reproductive systems, which may reflect roles of embryonic macrophages [29, [139][140][141][142]. The interpretation of the op/op phenotype is difficult because of transplacental trafficking of CSF-1, but recent evidence indicates that some embryonic macrophage populations can develop normally even when the mother is also op/op [143].…”