Differential Effects of Vitamins A and D on the Transcriptional Landscape of Human Monocytes during Infection

Abstract

Vitamin A and vitamin D are essential nutrients with a wide range of pleiotropic effects in humans. Beyond their well-documented roles in cellular differentiation, embryogenesis, tissue maintenance and bone/calcium homeostasis, both vitamins have attracted considerable attention due to their association with-immunological traits. Nevertheless, our knowledge of their immunomodulatory potential during infection is restricted to single gene-centric studies, which do not reflect the complexity of immune processes. In the present study, we performed a comprehensive RNA-seq-based approach to define the whole immunomodulatory role of vitamins A and D during infection. Using human monocytes as host cells, we characterized the differential role of both vitamins upon infection with three different pathogens: Aspergillus fumigatus, Candida albicans and Escherichia coli. Both vitamins showed an unexpected ability to counteract the pathogen-induced transcriptional responses. Upon infection, we identified 346 and 176 immune-relevant genes that were regulated by atRA and vitD, respectively. This immunomodulatory activity was dependent on the inflammatory stimulus, allowing us to distinguish regulatory patterns which were specific for each stimulatory setting. Moreover, we explored possible direct and indirect mechanisms of vitamin-mediated regulation of the immune response. Our findings highlight the importance of vitamin-monitoring in critically ill patients. Moreover, our results underpin the potential of atRA and vitD as therapeutic options for anti-inflammatory treatment.

Massive Effect on LncRNAs in Human Monocytes During Fungal and Bacterial Infections and in Response to Vitamins A and D

“…In comparison to the 24% of highly significantly regulated protein-coding mRNAs32, the number of differentially expressed lncRNAs is low. However, these few ncRNAs are much stronger regulated than the protein-coding mRNAs (see Fig.…”

“…About half of the 30 significantly expressed antisense ncRNAs are known to be related to immune response or infection and inflammation. Among them, we find AC073072.5 and RP11–536K7.5 to be antisense to the protein-based infection key player IL6 and receptor IL2RA, respectively32. Other antisense RNAs remain with unknown function.…”

“…1, plots in first column and first row). See also Klassert et al 32,. where the number of protein-coding genes being up- and down-regulated are comparable.…”

“…4A). Interestingly, these biological functions were also highlighted by Klassert et al ., when using the expression data of all protein-coding genes to perform gene ontology enrichment- and pathway analyses32.…”

“…32, are highly up-regulated during infection and down-regulated by atRA supply. Interestingly most of their antisense RNAs show a similarly strong behavior as described above for IL6 and AC073072.5 (see Fig.…”