Sexual dimorphism of monocyte transcriptome in individuals with chronic low-grade inflammation

Authors: SO, JISUN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; TAI, ALBERT - Tufts University; LICHTENSTEIN, ALICE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; WU, DAYONG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; LAMON-FAVA, STEFANIA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Biology of Sex Differences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/15/2021
Publication Date: 7/28/2021
Citation: So, J., Tai, A.K., Lichtenstein, A.H., Wu, D., Lamon-Fava, S. 2021. Sexual dimorphism of monocyte transcriptome in individuals with chronic low-grade inflammation. Biology of Sex Differences. 12:43. https://doi.org/10.1186/s13293-021-00387-y.
DOI: https://doi.org/10.1186/s13293-021-00387-y

Interpretive Summary: The prevalence of autoimmune diseases is higher in women than in men, while the rate of infectious disease is lower in women than in men. These differences in susceptibility to disease are likely due to gender differences in immune cell and are likely mediated by genetic information contained in the X and Y chromosomes. However, the gender-based pattern of gene expression in cell that participates in immune responses has not been characterized in humans. Monocytes are a type of white blood cell circulating in blood that fight certain infections and help other white blood cells remove dead or damaged tissues. They also regulate immunity against foreign substances. We isolated blood monocytes from 9 men and 12 postmenopausal women, all older than 50 years, and compared these cells' gene expression patterns. Several genes were expressed differently in monocytes isolated from women versus men. Of particular interest, we found that a greater number of genes involved in the interferon pathway were activated in female monocytes than male monocytes. Higher interferon activation has been linked to both autoimmune disease and resistance to viral infections. Therefore, our results suggest that the difference in immune functions between women and men may be due to higher activation of interferon in female than male monocytes.

Technical Abstract: Sexual dimorphism in the immune system is evidenced by a higher prevalence of autoimmune diseases in women and higher susceptibility to infectious diseases in men. However, the molecular basis of these sex-based differences is not fully understood. We have characterized the transcriptome profiles of peripheral blood monocytes from males and postmenopausal females with chronic low-grade inflammation. We identified 41 sexually differentially expressed genes [adjusted p value (FDR) < 0.1], including genes involved in immune cell activation (e.g., CEACAM1, FCGR2B, and SLAMF7) and antigen resentation (e.g., AIM2, CD1E, and UBA1), with a higher expression in females than males. Moreover, signaling pathways of immune or inflammatory responses, including interferon (IFN) signaling [z-score=2.45, -log(p)=3.88], were found to be more upregulated in female versus male monocytes, based on a set of genes exhibiting sex-biased expression (p < 0.03). The contribution of IFN signaling to the sexual transcriptional differences was further confirmed by direct comparisons of the monocyte sex biased genes with IFN signature genes (ISGs) that were previously curated in mouse macrophages. ISGs showed a greater overlap with female-biased genes than male-biased genes and a higher overall expression in female than male onocytes, particularly for the genes of antiviral and inflammatory responses to IFN. Given the role of IFN in immune defense and autoimmunity, our results suggest that sexual dimorphism in immune functions may be associated with a better priming of steady-state innate immune pathways in female than male monocytes. These findings highlight the role of sex on human immune transcriptome.