Prenatal stress challenge in mice: the role of vertically transmitted maternal glucocorticoids and immune cells in modulating offspring‘s immunity

• Applicants: Professorin Dr. Petra Clara Arck; Dr. Dimitra Zazara, since 5/2021
• Subject Area: Gynaecology and Obstetrics
• Term: from 2015 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 255154572

Epidemiological studies highlight that stress exposure during pregnancy increases the prevalence of infectious and chronic immune diseases later in life of the offspring. During pregnancy, tailored maternal immune and endocrine adaptations tightly control foetal development. These adaptations are highly susceptible to environmental cues, such as stress challenge. Insights into distinct pathways causally linking maternal mediators altered in response to stress challenge to an impaired foetal immune development are largely unknown. In mice, we could mimic the increased vulnerability of the adult offspring for chronic immune diseases (asthma) in response to prenatal stress. This effect was sex-specific, as female offspring were primarily affected. During the first funding period of the KFO296, we demonstrated that prenatal stress challenge tilts the maternal immune responses towards inflammation and activates the maternal hypothalamic-pituitary-adrenal axis, resulting in excess glucocorticoids not only in pregnant mice, but also their foetuses. Further, we established the detection of maternal cells in immune organs of the foetus and confirmed that they are retained until adulthood. As these cells occur at low frequencies, they are referred to as maternal microchimeric cells. Indeed, we observed a reduced frequency of maternal microchimeric cells in foetal bone marrow in response to stress. In depth analysis of the foetal bone marrow revealed an altered immune development upon stress, mirrored by decreased common myeloid progenitor cells and monocytes. Interestingly, in vitro experiments underscored that maternal microchimeric cells favour haematopoiesis towards the generation of monocytes. Further, when analysing bone marrow-derived haematopoietic stem cells from prenatally stressed adult offspring, a differential methylation of promoter regions was detectable, which included genes regulating myeloid cell differentiation. Noteworthy, lung development was also altered in prenatally stressed offspring. Based on these intriguing findings, we now seek to test the hypothesis that prenatal stress – via increased levels of maternal glucocorticoids and altered frequency and phenotype of maternal microchimeric cells - alters the lineage-specific epigenetic differentiation processes of haematopoietic stem cells, subsequently affecting offspring’s’ immunity. These alterations confer an increased susceptibility for infections, but also chronic immune diseases such as asthma or allergies.

• DFG Programme: Clinical Research Units
• Subproject of: KFO 296: Feto-maternal immune cross talk: Consequences for maternal and offspring's health
• Ehemalige Antragstellerin: Professorin Dr. Maria Emilia Solano, until 5/2021