Footmarks of Innate Immunity in the Ovary and CytokeratinPositive Cells as Potential Dendritic Cells Advances in Anatomy Embyrology and Cell Biology Paperback

This monograph introduces innate immunity as a second force in the ovary in addition to the endocrine system. Innate immunity appears to orchestrate follicular atresia, follicle rupture, and follicle transformation into a corpus luteum (CL) and CL regression through sterile inflammation and tissue repair. The concept is new. It centers on cytokeratin-positive (CK+) cells being recognized as a potential non lymphoid dendritic cell (DC) type. Part I describes morphological aspects of immune privilege starting with hamster ovary implants into the chicken chorioallantoic membrane with a non reactive mesenchyme. Follicular atresia and follicle rupture correspond to mild and moderate tissue damage in ovaries of small rodents and rabbits. Superovulations cause severe tissue damage through intra-ovarian oocyte release with follicle wall remnants in oedema, rupture of vessel walls and thrombosis. The complement system and neuropeptides might play regulatory roles. Part IIa analyzes intact ovaries (cows, human) for the appearance of CK+ cells. In the fetal ovary, sex cords give rise to CK+ cells in primordial follicles. In the adult ovary, CK+ cells are absent in preantral follicles and reappear in mature and regressing follicles. In the CL of early development, steroidogenic CK+ cells build a peripheral zone in the previous granulosa cell layer, and are uniformly distributed in the following stages. A microvascular CK+ cell type is seldom found. Part IIb characterizes the morphology and function of CK+ cells in vitro. Isolated from human preovulatory follicles, the epithelioid CK+ granulosa cell subtype regulates TLR4 and CD14 at 36 h of treatment with oxidized lipoprotein (oxLDL, 150 microg/ml); non-apoptotic cell death and the increase of reactive oxygen species occur. In contrast, the CK-negative (CK) granulosa cell type regulates the lectin-like oxLDL receptor 1 (LOX-1) and survival autophagy under oxLDL stimulation. Isolated from bovine CL, the epitheliold CK+ cell type 1 is disclosed as a microvascular cell type with a single nonmotile cilium. The microvascular CK+ type strongly upregulates intercellular contacts under treatment with interferon-gamma (IFN-gamma). In the CK- cell type 5 of granulosa cell-like appearance, IFN-gamma treatment supports cell proliferation, N-cadherin upregulation, and the dramatic increase in major histocompatibility complex II peptides (MHC II) by 80-fold compared to basal levels. Type 5 could have been converted from the steroidogenic CK+ cell type. We summarize and conclude: CK+ granulosa cells express functionally active TLR4, which sense danger signals, such as oxidative stress in preovulatory follicles, and trigger inflammatory and immunoregulatory pathways. The final outcome regulates follicle rupture and transformation into CL. Luteolysis could start by danger-sensing through the microvascular CK+ type 1 cells and the DC-like type 5 cells, both sensitive to IFN-gamma. The future will witness a novel strategy in the therapy of ovarian disorders such as anovulations, luteal phase insufficiency and autoimmune failures. Annotation The monograph introduces innate immunity as second authority in the ovary besides the endocrine system. Innate immunity appears to orchestrate follicular atresia, follicle rupture, follicle transformation into a corpus luteum (CL) and CL regression through nonsterile inflammation and tissue repair. The concept is new. It centres on cytokeratin-positive (CK+) cells being recognized as a potential nonlymphoid dendritic cell type (DC). Part I describes morphological aspects of immune privilege starting with active hamster ovary implants into the chicken chorioallantois membrane. Follicular atresia and follicle rupture correspond with mild and moderate tissue damage in ovaries of small rodents and rabbits. Superovulations cause severe tissue damage through intraovarian oocyte release with follicle wall remnants in oedema, rupture of vessel walls and thrombosis. The complement system and neuropeptides might play regulatory roles. Part IIa analyzes intact ovaries (cows, human) for the appearance of CK+ cells. In the foetal ovary, sex cords give rise to CK+ cells in primordial follicles. In the adult ovary, CK+ cells are absent in preantral follicles and reappear in mature and regressing follicles. In the CL of early development, steroidogenic CK+ cells build a peripheral zone in the previous granulosa cell layer, and uniformly distribute in the following stages. A microvessel-associated CK+ cell type is seldom found. Part IIb characterizes the morphology and function of CK+ cells in vitro. Isolated from human preovulatory follicles, the epithelioid CK+ granulosa cell subtype regulates TLR4 and CD14 at 36 h of treatment with oxidized lipoprotein (oxLDL, 150 mg/ml); nonapoptotic cell death and the increase of reactive oxygen species occur. In contrast, the CK-negative (CK-) granulosa cell type regulates the lectin-like oxLDL receptor 1 (LOX-1) and survival autophagy under oxLDL stimulation. Isolated from bovine CL, the epithelioid CK+ cell type 1 is disclosed as microvascular cell type with a single nonmotile cilium. The microvascular CK+ type strongly upregulates intercellular contacts under treatment with interferon- (IFN-). In the CK- cell type 5 of granulosa cell -like appearance, IFN- treatment supports cell proliferation, N-cadherin upregulation, and the dramatic increase in major histocompatibility complex II peptides (MHC II) by 80-fold compared to basal levels. Type 5 could have been conversed from the steroidogenic CK+ cell type. We summarize and conclude: CK+ granulosa cells express functionally active TLR4, which sense danger signals like oxidative stress in preovulatory follicles and trigger inflammatory and immunoregulatory pathways. The final outcome regulates follicle rupture and transformation into CL. Luteolysis could start by danger-sensing through the microvascular CK+ type 1 cells and the DC-like type 5 cells both sensitive to IFN-. The future will witness a novel strategy in the therapy of ovarian disorders like anovulations, luteal phase insufficiency, and autoimmune failures The monograph introduces innate immunity as second authority in the ovary besides the endocrine system. Innate immunity appears to orchestrate follicular atresia, follicle rupture, follicle transformation into a corpus luteum (CL) and CL regression through nonsterile inflammation and tissue repair. The concept is new. It centres on cytokeratin-positive (CK ) cells being recognized as a potential nonlymphoid dendritic cell type (DC). Part I describes morphological aspects of immune privilege starting with areactive hamster ovary implants into the chicken chorioallantois membrane. Follicular atresia and follicle rupture correspond with mild and moderate tissue damage in ovaries of small rodents and rabbits. Superovulations cause severe tissue damage through intraovarian oocyte release with follicle wall remnants in oedema, rupture of vessel walls and thrombosis. The complement system and neuropeptides might play regulatory roles. Part IIa analyzes intact ovaries (cows, human) for the appearance of CK cells. In the foetal ovary, sex cords give rise to CK cells in primordial follicles. In the adult ovary, CK cells are absent in preantral follicles and reappear in mature and regressing follicles. In the CL of early development, steroidogenic CK cells build a peripheral zone in the previous granulosa cell layer, and uniformly distribute in the following stages. A microvessel-associated CK cell type is seldom found. Part IIb characterizes the morphology and function of CK cells in vitro. Isolated from human preovulatory follicles, the epithelioid CK granulosa cell subtype regulates TLR4 and CD14 at 36 h of treatment with oxidized lipoprotein (oxLDL, 150 mg/ml); nonapoptotic cell death and the increase of reactive oxygen species occur. In contrast, the CK-negative (CK-) granulosa cell type regulates the lectin-like oxLDL receptor 1 (LOX-1) and survival autophagy under oxLDL stimulation. Isolated from bovine CL, the epithelioid CK cell type 1 is disclosed as microvascular cell type with a single nonmotile cilium. The microvascular CK type strongly upregulates intercellular contacts under treatment with interferon- (IFN-). In the CK- cell type 5 of granulosa cell -like appearance, IFN- treatment supports cell proliferation, N-cadherin upregulation, and the dramatic increase in major histocompatibility complex II peptides (MHC II) by 80-fold compared to basal levels. Type 5 could have been conversed from the steroidogenic CK cell type. We summarize and conclude: CK granulosa cells express functionally active TLR4, which sense danger signals like oxidative stress in preovulatory follicles and trigger inflammatory and immunoregulatory pathways. The final outcome regulates follicle rupture and transformation into CL. Luteolysis could start by danger-sensing through the microvascular CK type 1 cells and theDC-like type 5 cells both sensitive to IFN-. The future will witness a novel strategy in the therapy of ovarian disorders like anovulations, luteal phase insufficiency, and autoimmune failures The cyclic ovary can be seen as a site of tissue damage, repair and precisely controlled tissue homeostasis, as long ovulation and luteolysis can be compared with acute and chronic inflammation. Innate immunity appears to be a powerful force in the endocrine system, representing a novel concept. In this monograph, remarkable evidence is given for the immune-privileged ovary being an implant on the chicken chorioallantoic membrane with an areactive mesenchyme. Mild to severe tissue damages due to follicular atresia, follicular rupture, or intraovarian oocyte release do no lasting harm. The most exciting part relates to the analysis of cytokeratin-positive (CK + ) cells, comparing the fate mapping of this cell type from the fetal ovary to the adult organ. Findings on toll-like receptor 4 regulation and interferon-gamma-dependent positive effects indicate that CK + cells from human preovulatory follicles and bovine corpora lutea have similarities with nonlymphoid dendritic cells, a discovery that has the makings of a top story in basic and clinical research on the ovary. Footmarks of Innate Immunity in the Ovary and Cytokeratin-Positive Cells as Potential Dendritic Cells 4 Preface 6 Abstract 8 Acknowledgements 10 Contents 12 Abbreviations 14 Chapter 1: Background 18 Chapter 2: Materials and Methods 24 Chapter 3: Footmarks of INIM 33 Chapter 4: Cytokeratin-Positive Cells (CK+) as Potential Dendritic Cells 51 Chapter 5: Characterization of Isolated CK+ Cells 61 Chapter 6: Working Hypothesis and Challenges 93 Chapter 7: Clinical Perspectives 99 Chapter 8: Concluding Summary and Remarks 102 References 104 Index 115 Front Matter....Pages i-xv Background....Pages 1-6 Materials and Methods....Pages 7-15 Footmarks of INIM....Pages 17-34 Cytokeratin-Positive Cells (CK + ) as Potential Dendritic Cells....Pages 35-44 Characterization of Isolated CK + Cells....Pages 45-76 Working Hypothesis and Challenges....Pages 77-82 Clinical Perspectives....Pages 83-85 Concluding Summary and Remarks....Pages 87-88 Back Matter....Pages 89-110