Immunity: Cell microenvironment can affect gene expression of inflammatory cells and regulate immune response!

The human body responds to various stimuli encountered during development and homeostasis mediation through innate immune cells (such as macrophages), and its transcriptional plasticity is the basis for its complex functions
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This dynamic change of gene expression is not only determined by genetic lineage, but also depends on the expression changes of transcription factors such as promoters and enhancers

It is worth noting that many functions of macrophages are achieved by stimulating cytotoxic cells with type I interferon (IFN I)
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Therefore, the prevention of tissue damage has also become an important part of the inflammatory process, and this regulation can be achieved through changes in the expression levels of the above-mentioned genes

Recently, "Immunity" magazine published online research results of the research group of Renato Ostuni of the University of San Rafael in Italy, Vita-Salute, titled "A PGE2-MEF2A axis enables context-dependent control of inflammatory gene expression"
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The study revealed the basic principles of PGE2 signaling to control the transcription of inflammatory genes through genome and functional analysis, and determined the determinants of PGE2-driven immune regulation in macrophages

Researchers used lipopolysaccharide (LPS) and PEG2 or IL-10/IL-4 to stimulate mouse bone marrow-derived macrophages (BMDM), and analyzed their gene expression differences by RNA-seq
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The results showed that in the presence of LPS stimulation, PGE2, IL-10 and IL-4 mediate different LPS-induced genome expression

PGE2 antagonizes LPS-induced inflammatory gene expression

PGE2 antagonizes LPS-induced inflammatory gene expression PGE2 antagonizes LPS-induced inflammatory gene expression

So, how is the regulation effect of PGE2 realized? Studies have shown that PGE2 has no significant effect on the signal transduction pathway, while chromatin immunoprecipitation coupled sequencing (ChIP-seq) and the use of sequencing (ATAC-seq) experimental tests suggest that PGE2 mediates the functional inactivation of the inflammatory gene enhancer MEF2
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After further verification in macrophages, the researchers confirmed that PEG2 can functionally inactivate MEF2A

PGE2 controls inflammation genes through MEF2A

PGE2 controls inflammation genes through MEF2A PGE2 controls inflammation genes through MEF2A

On the other hand, the researchers knocked down MEF2A in macrophages and found that the loss of MEF2A caused the functional inactivation of the inflammatory gene enhancer, inhibited the expression of IFN-β, and thus inhibited the macrophage-mediated inflammatory response
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ChIP-seq analysis showed that PGE2 partially inhibited the expression of verification genes by antagonizing the activation of MEF2A transcriptional chaperone ERK5

PGE2 targets MEF2A through ERK5

PGE2 targets MEF2A through ERK5 PGE2 targets MEF2A through ERK5

All in all, this study analyzed the genomic characteristics of lipopolysaccharide (LPS)-induced genes and found that PGE2 can inhibit its expression by antagonizing the inflammatory gene enhancer MEF2A, and eliminate the innate immune response induced by IFN I after contact stimulation
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Therefore, antagonistic environmental factors are important regulators of inflammatory gene expression, as well as a key link in providing immune protection and preventing tissue damage
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The PGE2-MEF2A axis in this study can be used as a target for environment-dependent inflammation control, making it possible to control the environment-dependent control of inflammatory gene expression

Original source:

Original source:

Francesco Cilenti, et al.

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