Sex-dimorphic gene regulation in murine macrophages across niches

Abstract

Macrophages are a key cell type of the innate immune system and are involved at all steps of inflammation: (i) they present antigens to initiate inflammation, (ii) they clear up foreign bodies through phagocytosis, and (iii) they resolve inflammation by removing or deactivating mediator cells. Many subtypes of macrophages have been identified, classified by their niche and/or embryonic origin. In order to better develop therapies for conditions with macrophage dysfunction, it is crucial to decipher potential sex-differences in key physiological mediators of inflammation so that treatment efficacy can be ensured regardless of biological sex. Here, we conduct a meta-analysis approach of transcriptomics datasets for male vs. female mouse macrophages across 8 niches to characterize conserved sex-dimorphic pathways in macrophages across origins and niches. For this purpose, we leveraged new and publicly available RNA-sequencing datasets from murine macrophages, preprocessed these datasets and filtered them based on objective QC criteria, and performed differential gene expression analysis using sex as the covariate of interest. Differentially expressed (DE) genes were compared across datasets and macrophage subsets, and functional enrichment analysis was performed to identify sex-specific functional differences. Consistent with their presence on the sex chromosomes, three genes were found to be differentially expressed across all datasets (i.e. Xist, Eif2s3y, and Ddx3y). More broadly, we found that female-biased pathways across macrophage niches are more consistent than male-biased pathways, specifically relating to components of the extracellular matrix. Our findings increase our understanding of transcriptional similarities across macrophage niches and underscore the importance of including sex as a biological variable in immune-related studies. HighlightsO_LIAcross 17 independently transcriptomic macrophage datasets, three genes are always differentially expressed between males and females: Ddx3y, Eif2s3y, and Xist. C_LIO_LIJaccard analysis reveals female macrophages have more stereotypical transcriptional profile than male macrophages across niches. C_LIO_LIFunctional enrichment analyses show that female-biased pathways across macrophage subtypes are enriched for extracellular matrix-related genes. C_LI