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Depletion and Reconstitution of Macrophages in Mice
Published on: August 1, 2012
MGMT deficiency augments STING-mediated inflammatory responses accompanied by metabolic alterations in macrophages
Pornrat Kongkavitoon1,2, Atsadang Boonmee1,3, Thitiporn Pattarakankul1,4
1Department of Microbiology, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand.
Abstract:
The cGAS-STING pathway senses cytosolic DNA derived from both pathogens and host cells and plays a central role in innate immune responses. O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that removes alkylation-induced DNA lesions and modulates macrophage inflammatory responses. Here, we investigated the role of MGMT in macrophage responses to STING activation. Bone marrow-derived macrophages (BMMs) from Lyz2ΔMgmt mice produced higher levels of IL6, TNFα, and IFNβ following stimulation with the STING agonist DMXAA, accompanied by increased phosphorylation of TBK1 and IRF3. Lyz2ΔMgmt BMMs also exhibited increased expression of CD86, CD40, and CD120a (TNFRI), but reduced MHC class II expression. Metabolic flux analysis revealed enhanced mitochondrial oxidative respiration, increased ATP production, and greater maximal respiratory capacity, whereas glycolytic capacity remained unchanged. In addition, DMXAA-stimulated Lyz2ΔMgmt BMMs displayed increased γH2AX levels and reduced activation of the energy sensor AMPK and autophagy. Transcriptomic analysis further identified enrichment of pathways associated with cellular respiration. Collectively, these findings indicate that MGMT deficiency is associated with enhanced STING-induced inflammatory responses, altered cellular metabolism, and increased DNA damage in macrophages.
Insights
O6-methylguanine-DNA methyltransferase (MGMT) deficiency enhances macrophage inflammatory responses to STING activation. This involves altered cellular metabolism, increased DNA damage, and heightened production of key inflammatory cytokines.
Area of Science:
- Immunology
- Cellular Metabolism
- DNA Repair
Background:
- The cGAS-STING pathway is crucial for sensing cytosolic DNA and initiating innate immunity.
- O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that influences inflammatory responses.
- The role of MGMT in macrophage responses to STING activation requires further investigation.
Purpose of the Study:
- To investigate the role of MGMT in macrophage responses to STING activation.
- To elucidate the impact of MGMT deficiency on STING-mediated inflammatory signaling and cellular metabolism in macrophages.
Main Methods:
- Utilized bone marrow-derived macrophages (BMMs) from Lyz2ΔMgmt mice.
- Stimulated macrophages with the STING agonist DMXAA.
- Performed metabolic flux analysis, western blotting, flow cytometry, and transcriptomic analysis.
Main Results:
- Lyz2ΔMgmt BMMs showed elevated IL6, TNFα, and IFNβ production upon STING activation.
- Increased phosphorylation of TBK1 and IRF3 was observed in Lyz2ΔMgmt BMMs.
- Enhanced mitochondrial respiration, increased ATP production, and elevated DNA damage (γH2AX) were noted in MGMT-deficient macrophages.
- Reduced AMPK activation and autophagy were also observed.
Conclusions:
- MGMT deficiency potentiates STING-induced inflammatory responses in macrophages.
- MGMT deficiency alters macrophage cellular metabolism, favoring oxidative respiration.
- MGMT deficiency leads to increased DNA damage and impaired energy sensing pathways during STING activation.
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