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Int J Biol Sci 2024; 20(3):1004-1023. doi:10.7150/ijbs.87057 This issue Cite

Research Paper

Inactivation of MST1/2 Controls Macrophage Polarization to Affect Macrophage-Related Disease via YAP and Non-YAP Mechanisms

Yina An1, Shuyu Tan1, Pu Zhang1, Jingjing Yang1, Kezhi Wang1, Ruicheng Zheng2, Lu Qiao2, Yang Wang2,✉, Yanjun Dong1,✉

1. Department of Basic Veterinary Medicine, College of Veterinary Medicine, China Agricultural University; Beijing, 100193, China.
2. Beijing Key Laboratory of Detection Technology for Animal-Derived Food Safety, College of Veterinary Medicine, China Agricultural University; Beijing, 100193, China.

✉ Corresponding authors: yanjundedu.cn (YD); wangyangedu.cn (YW).

Citation:
An Y, Tan S, Zhang P, Yang J, Wang K, Zheng R, Qiao L, Wang Y, Dong Y. Inactivation of MST1/2 Controls Macrophage Polarization to Affect Macrophage-Related Disease via YAP and Non-YAP Mechanisms. Int J Biol Sci 2024; 20(3):1004-1023. doi:10.7150/ijbs.87057. https://www.ijbs.com/v20p1004.htm
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Abstract

Graphic abstract

Macrophage polarization is a critical process that regulates in inflammation, pathogen defense, and tissue repair. Here we demonstrate that MST1/2, a core kinase of Hippo pathway and a recently identified regulator of inflammation, plays a significant role in promoting M2 polarization. We provide evidence that inhibition of MST1/2, achieved through either gene-knockout or pharmacological treatment, leads to increased M1 polarization in a YAP-dependent manner, resulting in the development of M1-associated inflammatory disorders. Moreover, MST1/2 inhibition also leads to a substantial reduction in M2 polarization, but this occurs through the STAT6 and MEK/ERK signaling. The STAT6 is independent of YAP, but MEK/ERK is dependent of YAP. Consistent with these observations, both MST1/2-conditional knockout mice and wild-type mice treated with XMU-MP-1, a chemical inhibitor of MST1/2, exhibited reduced M2-related renal fibrosis, while simultaneously displaying enhanced LPS-mediated inflammation and improved clearance of MCR3-modified gram-negative bacteria. These findings uncover a novel role of MST1/2 in regulating macrophage polarization and establish it as a potential therapeutic target for the treatment of macrophage-related fibrotic diseases.

Keywords: MST1/2, macrophage polarization, inflammatory disease, bacterial infection, UUO

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APA
An, Y., Tan, S., Zhang, P., Yang, J., Wang, K., Zheng, R., Qiao, L., Wang, Y., Dong, Y. (2024). Inactivation of MST1/2 Controls Macrophage Polarization to Affect Macrophage-Related Disease via YAP and Non-YAP Mechanisms. International Journal of Biological Sciences, 20(3), 1004-1023. https://doi.org/10.7150/ijbs.87057.

ACS
An, Y.; Tan, S.; Zhang, P.; Yang, J.; Wang, K.; Zheng, R.; Qiao, L.; Wang, Y.; Dong, Y. Inactivation of MST1/2 Controls Macrophage Polarization to Affect Macrophage-Related Disease via YAP and Non-YAP Mechanisms. Int. J. Biol. Sci. 2024, 20 (3), 1004-1023. DOI: 10.7150/ijbs.87057.

NLM
An Y, Tan S, Zhang P, Yang J, Wang K, Zheng R, Qiao L, Wang Y, Dong Y. Inactivation of MST1/2 Controls Macrophage Polarization to Affect Macrophage-Related Disease via YAP and Non-YAP Mechanisms. Int J Biol Sci 2024; 20(3):1004-1023. doi:10.7150/ijbs.87057. https://www.ijbs.com/v20p1004.htm

CSE
An Y, Tan S, Zhang P, Yang J, Wang K, Zheng R, Qiao L, Wang Y, Dong Y. 2024. Inactivation of MST1/2 Controls Macrophage Polarization to Affect Macrophage-Related Disease via YAP and Non-YAP Mechanisms. Int J Biol Sci. 20(3):1004-1023.

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