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Male sex affects type I/type II interferon response of neutrophils during hepatic Amebiasis

ABSTRACT: Hepatic amebiasis, a serious complication caused by the parasite Entamoeba histolytica, predominantly affects men. Earlier research in the murine disease model indicated that testosterone modulates an intense immune reaction, triggering destructive immunopathological changes in the liver. Inflammatory monocytes expressing proinflammatory chemokines, crucial for neutrophil recruitment, worsen this process. This study examines sex-related variances in neutrophils during hepatic amebiasis in a mouse model. Male subjects exhibited higher levels and recruitment of neutrophils compared to females. Androgens directly contributed to this bias, enhancing neutrophil recruitment and retarding maturation in response to infection. Transcriptomic analysis revealed diminished type I and II interferon-stimulated gene expression and reduced activation pathways in male neutrophils versus female neutrophils. Upon ex-vivo stimulation, female human neutrophils showed higher expression of a key type I interferon-stimulated gene (viperin/RSAD2) at the protein level, which was similar in mice after infection, and suppressed by testosterone. In male mice with hepatic amebiasis, sex-dependent factors led to recruitment of less active neutrophils, intensifying immunopathological damage to liver tissue. This sex disparity and testosterone's impact on interferon-stimulated genes hold implications beyond hepatic amebiasis, potentially influencing broader areas, including viral infectious diseases

ORGANISM(S): Mus musculus

PROVIDER: GSE242045 | GEO | 2024/01/10

REPOSITORIES: GEO

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Project description:Despite sharing much of their genomes, males and females are often highly dimorphic, reflecting at least in part the resolution of sexual conflict in response to sexually antagonistic selection. Sexual dimorphism arises owing to sex differences in gene expression, and steroid hormones are often invoked as a proximate cause of sexual dimorphism. Experimental elevation of androgens can lead to masculinization of behavior, physiology, and gene expression, but knowledge of the role of hormones remains incomplete, including how the sexes differ in their gene expression in response to exposure to hormones. We addressed these questions in a bird species with a long history of behavioral endocrinological and ecological study, the dark-eyed junco (Junco hyemalis), using a species-specific microarray. Focusing on two brain regions involved in sexually dimorphic behavior and regulation of hormone secretion, we identified 1,639 genes that differed in expression by sex in the ventromedial telencephalon and 768 in hypothalamus. In response to experimentally elevated testosterone, females exhibited a more “male-like” expression pattern than control females; unexpectedly, male expression patterns became more “female-like” rather than hyper-masculinized when compared to control males. This sex difference in pattern arose both because testosterone altered regulation of different genes in each sex and because testosterone altered regulation of the same genes differentially, i.e., up in one sex, down in the other. Hormonally regulated gene expression is a key genetic and physiological mechanism underlying sexual dimorphism, and further study should help to explain how it relates to the resolution of sexual conflict. Males and females can be highly dimorphic in metabolism and physiology despite sharing nearly identical genomes, and males and females both respond phenotypically to elevated testosterone, a steroid hormone that alters gene expression. Only recently has it become possible to learn how a hormone like testosterone affects global gene expression in non-model systems, and whether it affects the same genes in males and females. To investigate the transcriptional mechanisms by which testosterone exerts its metabolic and physiological effects on the periphery, we compared gene expression by sex and in response to experimentally elevated testosterone in a well-studied bird species, the dark-eyed junco (Junco hyemalis). We identified 324 genes in the liver, and 733 in the pectoralis muscle that were differentially expressed between males and females. In addition, we identified 1,872 genes that were differentially expressed between testosterone-treated and control individuals in at least one tissue and sex. Testosterone-treatment altered the expression of only130 genes in both males and females in the same tissue. These substantial differences in transcriptional response to testosterone suggest that males and females may employ different pathways when responding to elevated testosterone, despite the fact that many phenotypic effects of experimentally elevated testosterone are similar in the sexes. In contrast, of the 130 genes that were affected by testosterone-treatment in both sexes, 78% were regulated in the same direction (e.g. either higher or lower in testosterone-treated than control males and females). Thus, it appears that testosterone acts through both unique and shared transcriptional pathways in males and females, suggesting multiple mechanisms by which sexual conflict can be mediated.

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Male sex affects type I/type II interferon response of neutrophils during hepatic Amebiasis

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