The Activation of M1 Macrophages is Associated with the JNK-m6A-p38 Axis in Chronic Obstructive Pulmonary Disease.

Abstract

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.

• Authors: Tingting Hu, Nannan Pang, Zheng Li, Dan Xu, Jing Jing, Fengsen Li, Jianbing Ding, Jing Wang, Min Jiang
• Journal: International journal of chronic obstructive pulmonary disease (Int J Chron Obstruct Pulmon Dis) Vol. 18 Pg. 2195-2206 ( 2023) ISSN: 1178-2005 [Electronic] New Zealand
• PMID: 37822331 (Publication Type: Journal Article)
• Copyright: © 2023 Hu et al.

Chemical References

• p38 Mitogen-Activated Protein Kinases
• Cytokines

Topics

• Humans
• Mice
• Animals
• Pulmonary Disease, Chronic Obstructive (genetics, metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)
• Macrophages (metabolism)
• Cytokines (metabolism)
• Signal Transduction