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ATF3 Positively Regulates Antibacterial Immunity by Modulating Macrophage Killing and Migration Functions
Yuzhang Du1, Zhihui Ma1, Juanjuan Zheng1
1Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Abstract:
The clinical severity of Staphylococcus aureus (S. aureus) respiratory infection correlates with antibacterial gene signature. S. aureus infection induces the expression of an antibacterial gene, as well as a central stress response gene, thus activating transcription factor 3 (ATF3). ATF3-deficient mice have attenuated protection against lethal S. aureus pneumonia and have a higher bacterial load. We tested the hypothesis that ATF3-related protection is based on the increased function of macrophages. Primary marrow-derived macrophages (BMDM) were used in vitro to determine the mechanism through which ATF3 alters the bacterial-killing ability. The expression of ATF3 correlated with the expression of antibacterial genes. Mechanistic studies showed that ATF3 upregulated antibacterial genes, while ATF3-deficient cells and lung tissues had a reduced level of antibacterial genes, which was accompanied by changes in the antibacterial process. We identified multiple ATF3 regulatory elements in the antibacterial gene promoters by chromatin immunoprecipitation analysis. In addition, Wild type (WT) mice had higher F4/80 macrophage migration in the lungs compared to ATF3-null mice, which may correlate with actin filament severing through ATF3-targeted actin-modifying protein gelsolin (GSN) for the macrophage cellular motility. Furthermore, ATF3 positively regulated inflammatory cytokines IL-6 and IL-12p40 might be able to contribute to the infection resolution. These data demonstrate a mechanism utilized by S. aureus to induce ATF3 to regulate antibacterial genes for antimicrobial processes within the cell, and to specifically regulate the actin cytoskeleton of F4/80 macrophages for their migration.
Insights
Transcription factor 3 (ATF3) enhances macrophage function and antibacterial gene expression, improving protection against Staphylococcus aureus pneumonia. ATF3 deficiency impairs these protective mechanisms, leading to increased bacterial load.
Area of Science:
- Immunology
- Microbiology
- Molecular Biology
Background:
- Staphylococcus aureus (S. aureus) respiratory infections can be severe, with clinical outcomes correlating to specific antibacterial gene expression.
- The transcription factor 3 (ATF3) is induced by S. aureus infection and plays a role in the host's stress response.
- ATF3-deficient mice exhibit reduced protection against lethal S. aureus pneumonia and higher bacterial burdens, suggesting a critical role for ATF3 in host defense.
Purpose of the Study:
- To investigate the mechanism by which ATF3 confers protection against S. aureus pneumonia, focusing on macrophage function.
- To elucidate the role of ATF3 in regulating antibacterial gene expression and macrophage-mediated bacterial clearance.
- To explore the impact of ATF3 on macrophage migration and inflammatory cytokine production during S. aureus infection.
Main Methods:
- In vitro studies using primary bone marrow-derived macrophages (BMDM) to assess ATF3's effect on bacterial-killing ability.
- Chromatin immunoprecipitation (ChIP) analysis to identify ATF3 regulatory elements in antibacterial gene promoters.
- Comparison of macrophage migration (F4/80) and inflammatory cytokine (IL-6, IL-12p40) levels in wild-type and ATF3-null mice.
Main Results:
- ATF3 expression positively correlated with the expression of antibacterial genes, and its absence led to reduced levels of these genes.
- ATF3 was found to upregulate antibacterial genes, and mechanistic studies confirmed its role in enhancing antimicrobial processes.
- Wild-type mice showed increased F4/80 macrophage migration in lungs compared to ATF3-null mice, potentially mediated by gelsolin (GSN) regulation.
- ATF3 positively regulated inflammatory cytokines IL-6 and IL-12p40, suggesting a role in infection resolution.
Conclusions:
- S. aureus infection induces ATF3, which in turn upregulates antibacterial genes essential for intracellular antimicrobial processes.
- ATF3 regulates the actin cytoskeleton of F4/80 macrophages via gelsolin, enhancing their migration and contributing to host defense.
- ATF3 plays a crucial role in host protection against S. aureus pneumonia by modulating both direct antimicrobial activity and macrophage-mediated immune responses.
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