Subject(s)
Headache/physiopathology , Hypoglossal Nerve Diseases/physiopathology , Occipital Bone/physiopathology , Carcinoma, Hepatocellular/complications , Carcinoma, Hepatocellular/secondary , Giant Cell Arteritis/pathology , Headache/diagnosis , Headache/etiology , Humans , Hypoglossal Nerve Diseases/diagnosis , Hypoglossal Nerve Diseases/etiology , Liver Neoplasms/complications , Liver Neoplasms/secondary , Magnetic Resonance Imaging , Male , Middle Aged , Occipital Bone/pathology , SyndromeABSTRACT
The mammary gland undergoes development and regression over the course of the ovarian cycle under the regulation of ovarian hormones. Macrophages are implicated as local mediators of this tissue remodeling and may also affect immune surveillance and tumor incidence. To investigate cycle-related changes in macrophage phenotype, mammary gland cells from naturally cycling Cfms-Gfp mice recovered at estrus, metestrus, diestrus, and proestrus were analyzed by flow cytometry. Macrophage expression of MHCII was highest in the proestrus phase, with a 1.6-fold increase compared to the metestrus phase. Similarly, macrophage expression of CD204 was 1.9-fold higher at proestrus compared to estrus. Conversely, macrophage expression of NKG2D was increased at metestrus and diestrus by 7-fold and 5-fold, respectively, compared to estrus. To investigate hormonal regulation of macrophage phenotype, an ovariectomy and hormone replacement model was utilized. Ovariectomized mice were stimulated with exogenous estradiol and progesterone to induce early alveolar development, then given progesterone receptor antagonist RU486 to elicit alveolar bud regression. Progesterone and estradiol in combination reduced macrophage expression of MHCII and CD204 by 5-fold and 3-fold, respectively, and increased macrophage expression of NKG2D by 4-fold. Administration of RU486, following estradiol and progesterone, reversed the macrophage phenotype. These results reveal an essential requirement for ovarian hormones in regulating macrophage phenotype in the mammary gland and indicate that progesterone is particularly critical for controlling macrophage antigen presentation and immune surveillance capacity.
Subject(s)
Estrous Cycle/physiology , Gonadal Steroid Hormones/physiology , Macrophages/cytology , Mammary Glands, Animal/cytology , Animals , Estrous Cycle/drug effects , Female , Flow Cytometry , Gonadal Steroid Hormones/pharmacology , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Macrophages/drug effects , Macrophages/physiology , Mammary Glands, Animal/drug effects , Mice , Mice, Inbred C57BL , Mice, Transgenic , Ovary/metabolism , PhenotypeABSTRACT
Each ovarian cycle, the mammary gland epithelium rotates through a sequence of hormonally regulated cell proliferation, differentiation and apoptosis. These studies investigate the role of macrophages in this cellular turnover. Macrophage populations and their spatial distribution were found to fluctuate across the cycle. The number of macrophages was highest at diestrus, and the greatest number of macrophages in direct contact with epithelial cells occurred at proestrus. The physiological necessity of macrophages in mammary gland morphogenesis during the estrous cycle was demonstrated in Cd11b-Dtr transgenic mice. Ovariectomised mice were treated with estradiol and progesterone to stimulate alveolar development, and with the progesterone receptor antagonist mifepristone to induce regression of the newly formed alveolar buds. Macrophage depletion during alveolar development resulted in a reduction in both ductal epithelial cell proliferation and the number of alveolar buds. Macrophage depletion during alveolar regression resulted in an increased number of branch points and an accumulation of TUNEL-positive cells. These studies show that macrophages have two roles in the cellular turnover of epithelial cells in the cycling mammary gland; following ovulation, they promote the development of alveolar buds in preparation for possible pregnancy, and they remodel the tissue back to its basic architecture in preparation for a new estrous cycle.
