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The Activation of M1 Macrophages is Associated with the JNK-m6A-p38 Axis in Chronic Obstructive Pulmonary Disease
Tingting Hu1, Nannan Pang2, Zheng Li1
1Xinjiang Laboratory of Respiratory Disease Research, Traditional Chinese Medicine Hospital Affiliated to Xinjiang Medical University, Urumqi, 830000, People's Republic of China.
Background:
Excessive activation of M1 macrophages affects the chronic inflammatory response of the airways and leads to the development of chronic obstructive pulmonary disease (COPD). Therefore, it needs to be closely monitored and investigated. MAPK signaling pathway is involved in the activation of M1 macrophages, and N6-methyladenosine (m6A) is involved in the pathogenesis of COPD. However, it is unknown whether activation of the MAPK signaling pathway is mediated by m6A in M1 macrophages in COPD.
Methods:
The GEO data were analyzed using bioinformatics techniques to assess the differences between COPD and healthy individuals in the levels of M1 macrophages, their secreted cytokines, and m6A regulators. The MAPK signaling pathway was significantly enriched in the list of differentially regulated genes between COPD and healthy individuals. We further analyzed the correlation between M1 macrophages, m6A, and the MAPK signaling pathway. Next, blood samples from COPD and healthy individuals were collected and analyzed by using flow cytometry, ELISA, and RT-PCR. Western blotting was performed using CSE-induced THP-1 cells. COPD and healthy mice were used for Me-RIP sequencing and flow cytometry experiments. Validation of the results of the above bioinformatics analysis by molecular biology experiments and sequencing techniques.
Results:
We found that GEO data and blood specimens from COPD patients showed increased M1 macrophages, higher levels of IL-6 and TNF-α, and higher mRNA expression of key mediators of the MAPK signaling pathway (p38, ERK, and JNK). Western blotting showed increased expression of p38, ERK, and JNK in the CSE group. In contrast, the expression of m6A regulators was low. Also, M1 macrophages in COPD mice were hyperactivated and had reduced m6A modifications of p38, ERK, and JNK compared with control.
Conclusion:
m6A may be involved in M1 macrophage hyperactivation by regulating the MAPK signaling pathway, thereby influencing the development of COPD.
Insights
N6-methyladenosine (m6A) may regulate M1 macrophage activation via the MAPK signaling pathway, contributing to chronic obstructive pulmonary disease (COPD) pathogenesis. This study investigated the role of m6A in M1 macrophage hyperactivation in COPD.
Area of Science:
- Immunology
- Molecular Biology
- Respiratory Medicine
Background:
- Excessive M1 macrophage activation is implicated in airway chronic inflammation and COPD development.
- The MAPK signaling pathway is crucial for M1 macrophage activation.
- N6-methyladenosine (m6A) plays a role in COPD pathogenesis, but its specific role in M1 macrophages remains unclear.
Purpose of the Study:
- To investigate the potential role of m6A in mediating MAPK signaling pathway activation in M1 macrophages within the context of COPD.
- To explore the relationship between M1 macrophages, m6A modification, and MAPK signaling in COPD patients and animal models.
Main Methods:
- Bioinformatic analysis of GEO data to compare M1 macrophages, cytokines, and m6A regulators between COPD and healthy individuals.
- Correlation analysis between M1 macrophages, m6A, and MAPK signaling pathway.
- Experimental validation using flow cytometry, ELISA, RT-PCR, Western blotting, and Me-RIP sequencing in human samples and mouse models.
Main Results:
- COPD patients exhibited increased M1 macrophages, elevated IL-6 and TNF-α, and higher MAPK pathway mediator expression (p38, ERK, JNK).
- Reduced m6A regulator expression and decreased m6A modification of MAPK pathway components were observed in M1 macrophages from COPD patients and mice.
- CSE-induced THP-1 cells and COPD mice models confirmed increased M1 macrophage activation and altered m6A modification patterns.
Conclusions:
- m6A modification may be involved in the hyperactivation of M1 macrophages by regulating the MAPK signaling pathway.
- These findings suggest a novel mechanism by which m6A influences COPD development through M1 macrophage-mediated inflammation.
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