Year: 2025
Type: article
Abstract: Description Objective This work aims to understand how myeloid cell development and function are dysregulated in Down syndrome (DS). Introduction: Individuals with DS experience severe immune dysregulation, including altered myeloid cell function and hyperactive interferon (IFN) signaling. However, it’s unclear which phenotypes are cell-intrinsic effects of trisomy 21 (T21) or how IFN signaling impacts myeloid cell function in DS. Methods Induced pluripotent stem cells (iPSCs) generated from individuals with and without DS were used to create hematopoietic stem and progenitor cells (HSPCs). These HSPCs underwent myelopoiesis, and cell subsets were characterized by flow cytometry. Myeloid functions, such as phagocytosis and NET formation, were measured after stimulation in the presence or absence of IFNs. Results T21 samples showed lower ratio of mature to progenitor immune cells during myelopoiesis and impaired production of total myeloid cells and monocytes. IPSC-derived and primary T21 monocytes showed impaired phagocytosis of S. Aureus at baseline and after IFN treatment. Meanwhile, unstimulated and PMA-stimulated T21 neutrophils showed elevated and earlier NET formation. Conclusions T21 results in cell-intrinsic alterations in monocyte production and defects in phagocytosis of bacteria, both in the presence and absence of interferons. Elevated and earlier NET production suggest that T21 neutrophils are primed for NET formation. Funding Sources NIH grant R01AI150305, NIH grant R24OD035579, Linda Crnic Institute for Down Syndrome, Global Down Syndrome Foundation, and the Anna and John J Sie Foundation. Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)
Source: The Journal of Immunology
Authors: Brian F. Niemeyer, Eleanor C. Britton, Madeline Hipp, Pamela Navarrete, Angela Rachubinski, Joaquin M. Espinosa
Institution: University of Colorado Anschutz
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4416446990
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