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Transcriptional and Linkage Analyses Identify Loci that Mediate the Differential Macrophage Response to Inflammatory Stimuli and Infection


Macrophages provide a first line of defense against invading pathogens and play an important role in the initiation and resolution of immune responses. When in contact with pathogens or immune factors, such as cytokines, macrophages assume activation states that range between pro-inflammatory (classical activation) and anti-inflammatory (alternative activation). Even though it is known that macrophages from different individuals are biased towards one of the various activation states, the genetic factors that define individual differences in macrophage activation are not fully understood. Additionally, although macrophages are important in infectious disease pathogenesis, how individual differences in macrophage activation contribute to individual differences in susceptibility to infectious disease is just emerging. We used macrophages from genetically segregating mice to show that discrete transcriptional programs, which are modulated by specific genomic regions, modulate differences in macrophage activation. Murine macrophages differences in controlling Toxoplasma growth mapped to chromosome 3, proximal to the Guanylate binding protein (Gbp) locus that is known to modulate the murine macrophage response to Toxoplasma. Using a shRNA-mediated knockdown approach, we show that the DEAD box polypeptide 1 (Ddx1) modulates nitric oxide production in macrophages stimulated with interferon gamma and tumor necrosis factor. These findings are a step towards the identification of genes that regulate macrophage phenotypes and disease outcome.


Vyšlo v časopise: Transcriptional and Linkage Analyses Identify Loci that Mediate the Differential Macrophage Response to Inflammatory Stimuli and Infection. PLoS Genet 11(10): e32767. doi:10.1371/journal.pgen.1005619
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005619

Souhrn

Macrophages provide a first line of defense against invading pathogens and play an important role in the initiation and resolution of immune responses. When in contact with pathogens or immune factors, such as cytokines, macrophages assume activation states that range between pro-inflammatory (classical activation) and anti-inflammatory (alternative activation). Even though it is known that macrophages from different individuals are biased towards one of the various activation states, the genetic factors that define individual differences in macrophage activation are not fully understood. Additionally, although macrophages are important in infectious disease pathogenesis, how individual differences in macrophage activation contribute to individual differences in susceptibility to infectious disease is just emerging. We used macrophages from genetically segregating mice to show that discrete transcriptional programs, which are modulated by specific genomic regions, modulate differences in macrophage activation. Murine macrophages differences in controlling Toxoplasma growth mapped to chromosome 3, proximal to the Guanylate binding protein (Gbp) locus that is known to modulate the murine macrophage response to Toxoplasma. Using a shRNA-mediated knockdown approach, we show that the DEAD box polypeptide 1 (Ddx1) modulates nitric oxide production in macrophages stimulated with interferon gamma and tumor necrosis factor. These findings are a step towards the identification of genes that regulate macrophage phenotypes and disease outcome.


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