Abstract
Reactive Nitrogen Species (RNS) are a group of bactericidal molecules produced by macrophages in response to pathogens in a process called oxidative burst. Nitric oxide (NO−) is a member of RNS produced from arginine by inducible Nitric Oxide Synthase (iNOS) enzyme. The activity of iNOS and production of NO− by macrophages following stimulation is one of the indicators of macrophage polarization towards M1/proinflammatory. Production of NO− by bovine monocyte-derived macrophage (MDM) and mouse peritoneal macrophages has been shown to be strongly associated with host genetic with the heritability of 0.776 in bovine MDM and 0.8 in mouse peritoneal macrophages. However, the mechanism of genetic regulation of macrophage response has remained less explored. In the current study, the transcriptome of bovine MDMs was compared between two extreme phenotypes that had been classified as high and low responder based on NO− production. The results showed that 179 and 392 genes were differentially expressed (DE) between high and low responder groups at 3 and 18 hours after exposure to Escherichia coli, respectively. A set of 11 Transcription Factors (TFs) (STAT1, IRF7, SPI1, STAT4, IRF1, HIF1A, FOXO3, REL, NFAT5, HIC1, and IRF4) at 3 hours and a set of 13 TFs (STAT1, IRF1, HIF1A, STAT4, ATF4, TP63, EGR1, CDKN2A, RBL1, E2F1, PRDM1, GATA3, and IRF4) at 18 hours after exposure to E. coli were identified to be differentially regulated between the high and low responder phenotypes. These TFs were found to be divided into two clusters of inflammatory- and hypoxia-related TFs. Functional analysis revealed that some key canonical pathways such as phagocytosis, chemotaxis, antigen presentation, and cell-to-cell signalling are enriched among the over-expressed genes by high responder phenotype. Based on the results of this study, it was inferred that the functional characteristics of bovine MDMs are associated with NO-based classification. Since NO− production is strongly associated with host genetics, this study for the first time shows the distinct proinflammatory profiles of macrophages are controlled by the natural genetic polymorphism in an outbred population. In addition, the results suggest that genetics can be considered as a new dimension in the current model of macrophage polarization which is currently described by the combination of stimulants, only.
Highlights
The immune system is an intricate network of cells and molecules, providing several layers of protection against pathogens
Macrophages are present in tissues either before the exposure to pathogens, Tissue-Resident Macrophages (TRM), or they are transformed from monocytes after the exposure to pathogens, Monocyte-Derived Macrophages (MDM)[11,12,13]
326 genes were overexpressed in the high NO− responder group and 66 genes were more expressed in the low responder NO− group
Summary
The immune system is an intricate network of cells and molecules, providing several layers of protection against pathogens. Among cells and molecules of the immune system, macrophages are the cornerstone of the innate immune system They are equipped with a wide range of functions from pro-inflammatory (at the beginning of infection) to anti-inflammatory and wound healing (at the end of infection). The reductionist approach has been utilized to investigate the effect of host genetics on the in-vitro functional variation of bovine MDM in response to Escherichia coli (E. coli). The results showed that the genetics of the host determined 77% of the phenotypic variation in NO production[21] It is not known if individual variation in production of NO− in response to one stimulant is associated with overall distinct proinflammatory profiles of macrophages, similar to distinct macrophage inflammatory profile in response to different stimulants.
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