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TRAF3/STAT6 axis regulates macrophage polarization and tumor progression

Cell Death & Differentiation volume 30, pages 2005–2016 (2023)Cite this article

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Abstract

Converting tumor-associated macrophages (TAMs) from the M2 to the M1 phenotype is considered an effective strategy for cancer therapy. TRAF3 is known to regulate NF-κB signaling. However, the role of TRAF3 in TAM polarization has not yet been completely elucidated. Here, we found that ablation of TRAF3 increased M1 markers, iNOS, FGR and SLC4A7, while down-regulated M2 markers, CD206, CD36 and ABCC3, expression levels in macrophages. Moreover, TRAF3 deficiency enhanced LPS-induced M1 and abolished IL-4-induced macrophage polarization. Next, quantitative ubiquitomics assays demonstrated that among the quantitative 7618 ubiquitination modification sites on 2598 proteins, ubiquitination modification of IL-4 responding proteins was the most prominently reduced according to enrichment analysis. STAT6, a key factor of IL-4 responding protein, K450 and K129 residue ubiquitination levels were dramatically decreased in TRAF3-deficient macrophages. Ubiquitination assay and luciferase assay demonstrated that TRAF3 promotes STAT6 ubiquitination and transcriptional activity. Site mutation analysis revealed STAT6 K450 site ubiquitination played a vital role in TRAF3-mediated STAT6 activation. Finally, B16 melanoma mouse model demonstrated that myeloid TRAF3 deficiency suppressed tumor growth and lung metastasis in vivo. Taken together, TRAF3 plays a vital role in M2 polarization via regulating STAT6 K450 ubiquitination in macrophages.

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Fig. 1: Combined analysis of transcriptome and proteome revealed TRAF3 regulates M1/M2 macrophage polarization.
Fig. 2: TRAF3 deficiency decreased IL-4-induced M2 macrophage polarization and promotes LPS-induced M1 macrophage polarization.
Fig. 3: Quantitative ubiquitomics assays demonstrated that TRAF3 regulates IL-4 pathway.
Fig. 4: TRAF3 promotes STAT6 ubiquitination and enhances IL-4 induced STAT6 transcriptional activity.
Fig. 5: TRAF3 deficiency suppressed tumor induced M2 TAM polarization.
Fig. 6: Myeloid TRAF3 deficiency suppressed B16 melanoma tumorigenesis and lung metastasis in mouse model.
Fig. 7: TRAF3 regulates immune cell infiltration in B16 tumor model.

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Data availability

The datasets generated during the current study are available from the corresponding author on reasonable request.

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Funding

Funding

This study was supported by National Natural Science Foundation of China (Nos. 82273463, 82103181, 31971304), Natural Science Foundation of Hebei Province (Nos. H2022201065, H2022201067, C2020201052, H2021201028), Hebei Province Foundation for Returned Overseas Scholars (No. C20200305), Government Foundation of Clinical Medicine Talents Training Program of Hebei Province (No. 361007), Foreign Intelligence Introduction Project of Hebei Province (No. 360601), CAMS Innovation Fund for Medical Sciences (No. 2019-I2M-5-055), Science and Technology Research Project of Colleges in Hebei Province (No. QN2023008), Foundation of President of Hebei University under grant (No.202204) and Tumor Microecological Metabolism Regulation Research Innovation Team of Hebei University.

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Authors and Affiliations

  1. Central Laboratory, Affiliated Hospital of Hebei University, Baoding, 071000, Hebei, China

    Jian-Hong Shi, Li-Na Liu, Dan-Dan Song, Chen Ling, Fei-Xiang Wu, Ting-Ting Wang, Bin Liu & Yan Qin

  2. Clinical Medical College, Hebei University, Baoding, 071000, Hebei, China

    Jian-Hong Shi, Li-Na Liu, Dan-Dan Song, Ting-Ting Wang & Zhi-Yu Ni

  3. Hebei Collaborative Innovation Center of Tumor Microecological Metabolism Regulation, Baoding, 071000, Hebei, China

    Jian-Hong Shi, Bin Liu, Nai-Peng Cui, Yan Qin & Zhi-Yu Ni

  4. Hebei Key Laboratory of Cancer Radiotherapy and Chemotherapy, Baoding, 071000, Hebei, China

    Jian-Hong Shi, Bin Liu & Nai-Peng Cui

  5. Department of Breast Surgery, Affiliated Hospital of Hebei University, Baoding, 071000, Hebei, China

    Wen-Wen Liu & Nai-Peng Cui

  6. Department of Medical Oncology, Hengyang Third People’s Hospital, Hengyang, 421200, Hunan, China

    Chen Ling

  7. Hebei Key Laboratory of Precise Imaging of Inflammation Related Tumors, Baoding, 071000, Hebei, China

    Fei-Xiang Wu & Yan Qin

  8. Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, 100000, Beijing, China

    Zhi-Yu Ni

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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by J-HS, L-NL, D-DS, W-WL, CL, F-XW and T-TW. BL, N-PC, YQ and J-HS analyzed and interpreted the data. The first draft of the manuscript was written by J-HS and Z-YN and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Jian-Hong Shi, Yan Qin or Zhi-Yu Ni.

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The animal experiments were conducted according to the protocol approved by the Animal Ethical and Welfare Committee (AEWC) of Hebei University.

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Shi, JH., Liu, LN., Song, DD. et al. TRAF3/STAT6 axis regulates macrophage polarization and tumor progression. Cell Death Differ 30, 2005–2016 (2023). https://doi.org/10.1038/s41418-023-01194-1

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