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Modulation of M2 macrophage polarization by the crosstalk between Stat6 and Trim24
Tao Yu1, Shucheng Gan1, Qingchen Zhu1
1CAS Key Laboratory of Tissue Microenvironment and Tumor, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China.
Abstract:
Stat6 is known to drive macrophage M2 polarization. However, how macrophage polarization is fine-tuned by Stat6 is poorly understood. Here, we find that Lys383 of Stat6 is acetylated by the acetyltransferase CREB-binding protein (CBP) during macrophage activation to suppress macrophage M2 polarization. Mechanistically, Trim24, a CBP-associated E3 ligase, promotes Stat6 acetylation by catalyzing CBP ubiquitination at Lys119 to facilitate the recruitment of CBP to Stat6. Loss of Trim24 inhibits Stat6 acetylation and thus promotes M2 polarization in both mouse and human macrophages, potentially compromising antitumor immune responses. By contrast, Stat6 mediates the suppression of TRIM24 expression in M2 macrophages to contribute to the induction of an immunosuppressive tumor niche. Taken together, our findings establish Stat6 acetylation as an essential negative regulatory mechanism that curtails macrophage M2 polarization.
Insights
Acetylation of Signal transducer and activator of transcription 6 (Stat6) by CREB-binding protein (CBP) suppresses M2 macrophage polarization. Trim24 facilitates this acetylation, impacting antitumor immunity and tumor microenvironments.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Signal transducer and activator of transcription 6 (Stat6) is a key regulator of macrophage M2 polarization.
- The precise mechanisms by which Stat6 activity is fine-tuned remain incompletely understood.
Purpose of the Study:
- To elucidate the regulatory mechanisms controlling Stat6 activity during macrophage polarization.
- To investigate the role of Stat6 acetylation in macrophage M2 polarization and its implications for antitumor immunity.
Main Methods:
- Macrophage activation and polarization assays in mouse and human cells.
- Biochemical analyses including acetylation and ubiquitination assays.
- Western blotting and immunoprecipitation to study protein interactions.
- Gene expression analysis to assess TRIM24 and other relevant markers.
Main Results:
- Lysine 383 (Lys383) acetylation of Stat6 by CREB-binding protein (CBP) suppresses M2 polarization.
- The E3 ligase Trim24 promotes Stat6 acetylation by catalyzing CBP ubiquitination, enhancing CBP recruitment to Stat6.
- Loss of Trim24 leads to reduced Stat6 acetylation, increased M2 polarization, and potentially impaired antitumor responses.
- Stat6 suppresses TRIM24 expression in M2 macrophages, contributing to an immunosuppressive tumor niche.
Conclusions:
- Stat6 acetylation is an essential negative regulatory mechanism controlling macrophage M2 polarization.
- The Trim24-CBP-Stat6 axis represents a novel pathway for modulating macrophage phenotypes.
- Targeting this pathway could offer therapeutic strategies for enhancing antitumor immunity.
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