Life-long brain function and mental health are critically determined by developmental processes o... more Life-long brain function and mental health are critically determined by developmental processes occurring before birth. During mammalian pregnancy, maternal cells are transferred to the fetus. They are referred to as maternal microchimeric cells (MMc). Among other organs, MMc seed into the fetal brain, where their function is unknown. Here, we show that, in the offspring’s developing brain in mice, MMc express a unique signature of sensome markers, control microglia homeostasis and prevent excessive presynaptic elimination. Further, MMc facilitate the oscillatory entrainment of developing prefrontal-hippocampal circuits and support the maturation of behavioral abilities. Our findings highlight that MMc are not a mere placental leak out, but rather a functional mechanism that shapes optimal conditions for healthy brain function later in life.
The conception of how the immune system is organized has been significantly challenged over the l... more The conception of how the immune system is organized has been significantly challenged over the last years. It became evident that not all lymphocytes are mobile and recirculate through secondary lymphoid organs. Instead, subsets of immune cells continuously reside in tissues until being reactivated, e.g., by a recurring pathogen or other stimuli. Consequently, the concept of tissue-resident immunity has emerged, and substantial evidence is now available to support its pivotal function in maintaining tissue homeostasis, sensing challenges and providing antimicrobial protection. Surprisingly, insights on tissue-resident immunity in the barrier tissues of the female reproductive tract are sparse and only slowly emerging. The need for protection from vaginal and amniotic infections, the uniqueness of periodic tissue shedding and renewal of the endometrial barrier tissue, and the demand for a tailored decidual immune adaptation during pregnancy highlight that tissue-resident immunity ma...
The physiological process of male reproduction relies on the orchestration of neuroendocrine, imm... more The physiological process of male reproduction relies on the orchestration of neuroendocrine, immune, and energy metabolism. Spermatogenesis is controlled by the hypothalamic-pituitary-testicular (HPT) axis, which modulates the production of gonadal steroid hormones in the testes. The immune cells and cytokines in testes provide a protective microenvironment for the development and maturation of germ cells. The metabolic cellular responses and processes in testes provide energy production and biosynthetic precursors to regulate germ cell development and control testicular immunity and inflammation. The metabolism of immune cells is crucial for both inflammatory and anti-inflammatory responses, which supposes to affect the spermatogenesis in testes. In this review, the role of immunometabolism in male reproduction will be highlighted. Obesity, metabolic dysfunction, such as type 2 diabetes mellitus, are well documented to impact male fertility; thus, their impacts on the immune cells...
During mammalian pregnancy, immune cells are vertically transferred from mother to fetus. The fun... more During mammalian pregnancy, immune cells are vertically transferred from mother to fetus. The functional role of these maternal microchimeric cells (MMc) in the offspring is mostly unknown. Here we show a mouse model in which MMc numbers are either normal or low, which enables functional assessment of MMc. We report a functional role of MMc in promoting fetal immune development. MMc induces preferential differentiation of hematopoietic stem cells in fetal bone marrow towards monocytes within the myeloid compartment. Neonatal mice with higher numbers of MMc and monocytes show enhanced resilience against cytomegalovirus infection. Similarly, higher numbers of MMc in human cord blood are linked to a lower number of respiratory infections during the first year of life. Our data highlight the importance of MMc in promoting fetal immune development, potentially averting the threats caused by early life exposure to pathogens.
A wealth of innate and adaptive immune cells and hormones are involved in mounting tolerance towa... more A wealth of innate and adaptive immune cells and hormones are involved in mounting tolerance towards the fetus, a key aspect of successful reproduction. We could recently show that the specific cross talk between the pregnancy hormone progesterone and dendritic cells (DCs) is significantly engaged in the generation of CD4+ FoxP3+ regulatory T (Treg) cells while a disruption led to placental alterations and intra-uterine growth restriction. Apart from progesterone, also glucocorticoids affect immune cell functions. However, their functional relevance in the context of pregnancy still needs clarification. We developed a mouse line with a selective knockout of the glucocorticoid receptor (GR) on DCs, utilizing the cre/flox system. Reproductive outcome and maternal immune and endocrine adaptation of Balb/c-mated C57Bl/6 GRflox/floxCD11ccre/wt (mutant) females was assessed on gestation days (gd) 13.5 and 18.5. Balb/c-mated C57Bl/6 GRwt/wtCD11ccre/wt (wt) females served as controls. The n...
Acetaminophen (APAP, i.e. Paracetamol or Tylenol) is an over the counter drug, and hence, often s... more Acetaminophen (APAP, i.e. Paracetamol or Tylenol) is an over the counter drug, and hence, often self-medicated to treat fever or pain and generally recommended to pregnant women by their physicians. Recent epidemiological studies revealed an association between prenatal APAP use and an impaired children’s health, i.e. an increased risk for asthma. Thus, it was the aim of the present thesis project to establish a mouse model in order to study the effects of prenatal APAP use on liver toxicity and morbidity, the maternal immune and endocrine adaptation to pregnancy and placental morphology. Additionally, the impact on pregnancy outcome and fetal immune development have been investigated. Syngenic and allogenic-mated C57Bl/6J female mice were injected intraperitoneally with APAP (50 or 250 mg/kg) or PBS on gestational day 12.5, non-pregnant females served as controls. Pregnant mice were sacrificed either on gd 13.5 or 16.5, tissue from non-pregnant mice was obtained 24 or 96 hours post...
Pregnant women have been carefully observed during the COVID-19 pandemic, as the pregnancy-specif... more Pregnant women have been carefully observed during the COVID-19 pandemic, as the pregnancy-specific immune adaptation is known to increase the risk for infections. Recent evidence indicates that even though most pregnant have a mild or asymptomatic course, a severe course of COVID-19 and a higher risk of progression to diseases have also been described, along with a heightened risk for pregnancy complications. Yet, vertical transmission of the virus is rare and the possibility of placental SARS-CoV-2 infection as a prerequisite for vertical transmission requires further studies. We here assessed the severity of COVID-19 and onset of neonatal infections in an observational study of women infected with SARS-CoV-2 during pregnancy. Our placental analyses showed a paucity of SARS-CoV-2 viral expression ex vivo in term placentae under acute infection. No viral placental expression was detectable in convalescent pregnant women. Inoculation of placental explants generated from placentas of...
The emerging field of immunometabolism has substantially progressed over the last years and provi... more The emerging field of immunometabolism has substantially progressed over the last years and provided pivotal insights into distinct metabolic regulators and reprogramming pathways of immune cell populations in various immunological settings. However, insights into immunometabolic reprogramming in the context of reproduction are still enigmatic. During pregnancy, the maternal immune system needs to actively adapt to the presence of the fetal antigens, i.e., by functional modifications of distinct innate immune cell subsets, the generation of regulatory T cells, and the suppression of an anti-fetal effector T cell response. Considering that metabolic pathways have been shown to affect the functional role of such immune cells in a number of settings, we here review the potential role of immunometabolism with regard to the molecular and cellular mechanisms necessary for successful reproduction. Since immunometabolism holds the potential for a therapeutic approach to alter the course of ...
Pregnant women are at high risk for severe influenza disease outcomes, yet insights into the unde... more Pregnant women are at high risk for severe influenza disease outcomes, yet insights into the underlying mechanisms are limited. Here, we present models of H1N1 infection in syngenic and allogenic pregnant mice; infection in the latter mirrors the severe course of 2009 pandemic influenza in pregnant women. We found that the anti-viral immune response in the pregnant host was significantly restricted as compared to the non-pregnant host. This included a reduced type I interferon response as well as impaired migration of CD8(+) T cells into the lung. The multi-faceted failure to mount an anti-viral response in allogenic pregnant mice resulted in a less stringent selective environment that promoted the emergence of 2009 H1N1 virus variants that specifically counteract type I interferon response and mediate increased viral pathogenicity. These insights underscore the importance of influenza vaccination compliance in pregnant women and may open novel therapeutic avenues.
Life-long brain function and mental health are critically determined by developmental processes o... more Life-long brain function and mental health are critically determined by developmental processes occurring before birth. During mammalian pregnancy, maternal cells are transferred to the fetus. They are referred to as maternal microchimeric cells (MMc). Among other organs, MMc seed into the fetal brain, where their function is unknown. Here, we show that, in the offspring’s developing brain in mice, MMc express a unique signature of sensome markers, control microglia homeostasis and prevent excessive presynaptic elimination. Further, MMc facilitate the oscillatory entrainment of developing prefrontal-hippocampal circuits and support the maturation of behavioral abilities. Our findings highlight that MMc are not a mere placental leak out, but rather a functional mechanism that shapes optimal conditions for healthy brain function later in life.
The conception of how the immune system is organized has been significantly challenged over the l... more The conception of how the immune system is organized has been significantly challenged over the last years. It became evident that not all lymphocytes are mobile and recirculate through secondary lymphoid organs. Instead, subsets of immune cells continuously reside in tissues until being reactivated, e.g., by a recurring pathogen or other stimuli. Consequently, the concept of tissue-resident immunity has emerged, and substantial evidence is now available to support its pivotal function in maintaining tissue homeostasis, sensing challenges and providing antimicrobial protection. Surprisingly, insights on tissue-resident immunity in the barrier tissues of the female reproductive tract are sparse and only slowly emerging. The need for protection from vaginal and amniotic infections, the uniqueness of periodic tissue shedding and renewal of the endometrial barrier tissue, and the demand for a tailored decidual immune adaptation during pregnancy highlight that tissue-resident immunity ma...
The physiological process of male reproduction relies on the orchestration of neuroendocrine, imm... more The physiological process of male reproduction relies on the orchestration of neuroendocrine, immune, and energy metabolism. Spermatogenesis is controlled by the hypothalamic-pituitary-testicular (HPT) axis, which modulates the production of gonadal steroid hormones in the testes. The immune cells and cytokines in testes provide a protective microenvironment for the development and maturation of germ cells. The metabolic cellular responses and processes in testes provide energy production and biosynthetic precursors to regulate germ cell development and control testicular immunity and inflammation. The metabolism of immune cells is crucial for both inflammatory and anti-inflammatory responses, which supposes to affect the spermatogenesis in testes. In this review, the role of immunometabolism in male reproduction will be highlighted. Obesity, metabolic dysfunction, such as type 2 diabetes mellitus, are well documented to impact male fertility; thus, their impacts on the immune cells...
During mammalian pregnancy, immune cells are vertically transferred from mother to fetus. The fun... more During mammalian pregnancy, immune cells are vertically transferred from mother to fetus. The functional role of these maternal microchimeric cells (MMc) in the offspring is mostly unknown. Here we show a mouse model in which MMc numbers are either normal or low, which enables functional assessment of MMc. We report a functional role of MMc in promoting fetal immune development. MMc induces preferential differentiation of hematopoietic stem cells in fetal bone marrow towards monocytes within the myeloid compartment. Neonatal mice with higher numbers of MMc and monocytes show enhanced resilience against cytomegalovirus infection. Similarly, higher numbers of MMc in human cord blood are linked to a lower number of respiratory infections during the first year of life. Our data highlight the importance of MMc in promoting fetal immune development, potentially averting the threats caused by early life exposure to pathogens.
A wealth of innate and adaptive immune cells and hormones are involved in mounting tolerance towa... more A wealth of innate and adaptive immune cells and hormones are involved in mounting tolerance towards the fetus, a key aspect of successful reproduction. We could recently show that the specific cross talk between the pregnancy hormone progesterone and dendritic cells (DCs) is significantly engaged in the generation of CD4+ FoxP3+ regulatory T (Treg) cells while a disruption led to placental alterations and intra-uterine growth restriction. Apart from progesterone, also glucocorticoids affect immune cell functions. However, their functional relevance in the context of pregnancy still needs clarification. We developed a mouse line with a selective knockout of the glucocorticoid receptor (GR) on DCs, utilizing the cre/flox system. Reproductive outcome and maternal immune and endocrine adaptation of Balb/c-mated C57Bl/6 GRflox/floxCD11ccre/wt (mutant) females was assessed on gestation days (gd) 13.5 and 18.5. Balb/c-mated C57Bl/6 GRwt/wtCD11ccre/wt (wt) females served as controls. The n...
Acetaminophen (APAP, i.e. Paracetamol or Tylenol) is an over the counter drug, and hence, often s... more Acetaminophen (APAP, i.e. Paracetamol or Tylenol) is an over the counter drug, and hence, often self-medicated to treat fever or pain and generally recommended to pregnant women by their physicians. Recent epidemiological studies revealed an association between prenatal APAP use and an impaired children’s health, i.e. an increased risk for asthma. Thus, it was the aim of the present thesis project to establish a mouse model in order to study the effects of prenatal APAP use on liver toxicity and morbidity, the maternal immune and endocrine adaptation to pregnancy and placental morphology. Additionally, the impact on pregnancy outcome and fetal immune development have been investigated. Syngenic and allogenic-mated C57Bl/6J female mice were injected intraperitoneally with APAP (50 or 250 mg/kg) or PBS on gestational day 12.5, non-pregnant females served as controls. Pregnant mice were sacrificed either on gd 13.5 or 16.5, tissue from non-pregnant mice was obtained 24 or 96 hours post...
Pregnant women have been carefully observed during the COVID-19 pandemic, as the pregnancy-specif... more Pregnant women have been carefully observed during the COVID-19 pandemic, as the pregnancy-specific immune adaptation is known to increase the risk for infections. Recent evidence indicates that even though most pregnant have a mild or asymptomatic course, a severe course of COVID-19 and a higher risk of progression to diseases have also been described, along with a heightened risk for pregnancy complications. Yet, vertical transmission of the virus is rare and the possibility of placental SARS-CoV-2 infection as a prerequisite for vertical transmission requires further studies. We here assessed the severity of COVID-19 and onset of neonatal infections in an observational study of women infected with SARS-CoV-2 during pregnancy. Our placental analyses showed a paucity of SARS-CoV-2 viral expression ex vivo in term placentae under acute infection. No viral placental expression was detectable in convalescent pregnant women. Inoculation of placental explants generated from placentas of...
The emerging field of immunometabolism has substantially progressed over the last years and provi... more The emerging field of immunometabolism has substantially progressed over the last years and provided pivotal insights into distinct metabolic regulators and reprogramming pathways of immune cell populations in various immunological settings. However, insights into immunometabolic reprogramming in the context of reproduction are still enigmatic. During pregnancy, the maternal immune system needs to actively adapt to the presence of the fetal antigens, i.e., by functional modifications of distinct innate immune cell subsets, the generation of regulatory T cells, and the suppression of an anti-fetal effector T cell response. Considering that metabolic pathways have been shown to affect the functional role of such immune cells in a number of settings, we here review the potential role of immunometabolism with regard to the molecular and cellular mechanisms necessary for successful reproduction. Since immunometabolism holds the potential for a therapeutic approach to alter the course of ...
Pregnant women are at high risk for severe influenza disease outcomes, yet insights into the unde... more Pregnant women are at high risk for severe influenza disease outcomes, yet insights into the underlying mechanisms are limited. Here, we present models of H1N1 infection in syngenic and allogenic pregnant mice; infection in the latter mirrors the severe course of 2009 pandemic influenza in pregnant women. We found that the anti-viral immune response in the pregnant host was significantly restricted as compared to the non-pregnant host. This included a reduced type I interferon response as well as impaired migration of CD8(+) T cells into the lung. The multi-faceted failure to mount an anti-viral response in allogenic pregnant mice resulted in a less stringent selective environment that promoted the emergence of 2009 H1N1 virus variants that specifically counteract type I interferon response and mediate increased viral pathogenicity. These insights underscore the importance of influenza vaccination compliance in pregnant women and may open novel therapeutic avenues.
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