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1.
Front Immunol ; 15: 1368572, 2024.
Article in English | MEDLINE | ID: mdl-38698852

ABSTRACT

Introduction: Interferon-gamma (IFN-γ) is pivotal in orchestrating immune responses during healthy pregnancy. However, its dysregulation, often due to autoimmunity, infections, or chronic inflammatory conditions, is implicated in adverse reproductive outcomes such as pregnancy failure or infertility. Additionally, the underlying immunological mechanisms remain elusive. Methods: Here, we explore the impact of systemic IFN-γ elevation on cytotoxic T cell responses in female reproduction utilizing a systemic lupus-prone mouse model with impaired IFN-γ degradation. Results: Our findings reveal that heightened IFN-γ levels triggered the infiltration of CD8+T cells in the pituitary gland and female reproductive tract (FRT), resulting in prolactin deficiency and subsequent infertility. Furthermore, we demonstrate that chronic IFN-γ elevation increases effector memory CD8+T cells in the murine ovary and uterus. Discussion: These insights broaden our understanding of the role of elevated IFN-γ in female reproductive dysfunction and suggest CD8+T cells as potential immunotherapeutic targets in female reproductive disorders associated with chronic systemic IFN-γ elevation.


Subject(s)
CD8-Positive T-Lymphocytes , Interferon-gamma , Animals , Female , Mice , Pregnancy , CD8-Positive T-Lymphocytes/immunology , Disease Models, Animal , Infertility, Female/immunology , Interferon-gamma/metabolism , Lupus Erythematosus, Systemic/immunology , Mice, Inbred C57BL , Ovary/immunology , Pituitary Gland/immunology , Pituitary Gland/metabolism , Prolactin/metabolism , Uterus/immunology
2.
J Pathol ; 260(3): 276-288, 2023 07.
Article in English | MEDLINE | ID: mdl-37185821

ABSTRACT

The effect of cytokines on non-traditional immunological targets under conditions of chronic inflammation is an ongoing subject of study. Fatigue is a symptom often associated with autoimmune diseases. Chronic inflammatory response and activated cell-mediated immunity are associated with cardiovascular myopathies which can be driven by muscle weakness and fatigue. Thus, we hypothesize that immune dysfunction-driven changes in myocyte mitochondria may play a critical role in fatigue-related pathogenesis. We show that persistent low-level expression of IFN-γ in designated IFN-γ AU-Rich Element deletion mice (ARE mice) under androgen exposure resulted in mitochondrial and metabolic deficiencies in myocytes from male or castrated ARE mice. Most notably, echocardiography unveiled that low ejection fraction in the left ventricle post-stress correlated with mitochondrial deficiencies, explaining how heart function decreases under stress. We report that inefficiencies and structural changes in mitochondria, with changes to expression of mitochondrial genes, are linked to male-biased fatigue and acute cardiomyopathy under stress. Our work highlights how male androgen hormone backgrounds and active autoimmunity reduce mitochondrial function and the ability to cope with stress and how pharmacological blockade of stress signal protects heart function. These studies provide new insight into the diverse actions of IFN-γ in fatigue, energy metabolism, and autoimmunity. © 2023 The Pathological Society of Great Britain and Ireland. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.


Subject(s)
Androgens , Interferon-gamma , Animals , Male , Mice , Androgens/metabolism , Cytokines/metabolism , Inflammation/metabolism , Mitochondria/metabolism , Muscle Cells/metabolism
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