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Advanced Glycated End Products Alter Neutrophil Effect on Regulation of CD4+ T Cell Differentiation Through Induction of Myeloperoxidase and Neutrophil Elastase Activities

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Abstract

CD4+ T cell subset imbalance plays an important role in the development of diabetic complications. Neutrophils have recently been known as the regulator of CD4+ T cell differentiation. However, whether neutrophils affect CD4+ T cell population in diabetes is still elusive. In this study, we investigated the effect of neutrophils stimulated with advanced glycated end products (AGEs), the marker of diabetes, on CD4+ T cell differentiation and its underlying mechanism. Our data showed that the cultural medium of healthy adult neutrophils treated with AGEs increased expressions of both Th1 (IFN-γ) and Th17 (IL-17) phenotypes and the transcription factors of Th1 (Tbet) and Th17 (RORγt) in naive CD4+T cells and CD4+CD25+FoxP3+ (Treg) T cells in vitro. Next, we found that AGEs induced the generations of myeloperoxidase (MPO) and neutrophil elastase (NE) in neutrophils; inhibition of MPO or NE attenuated the effect of AGE-stimulated neutrophils on CD4+ T cell bias. Furthermore, receptor for AGEs (RAGE) inhibitor interrupted AGE-induced MPO and NE expressions, but MPO and NE inhibitions did not change AGE-increased RAGE gene expression. These results suggested that AGEs drive the effect of neutrophils on CD4+ T cell differentiation into pro-inflammatory program through inducing MPO and NE productions in neutrophils, which is mediated by AGE–RAGE interaction.

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Abbreviations

AGEs:

Advanced glycated end products

MPO:

Myeloperoxidase

NE:

Neutrophil elastase

RAGE:

Receptor for AGEs

Treg:

Regulatory T cells

NET:

Neutrophil extracellular traps

ROR:

Retinoic orphan receptor

IFN-γ:

Interferon-gamma

BSA:

Bovine serum albumin

PBS:

Phosphate-buffered saline

ICS:

Intracellular cytokine staining

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

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Acknowledgements

We are grateful for the participants who volunteered for this study and the physicians and nurses in the Department of Neurology for their assistances during the execution of the work.

Funding

The study was supported by Talent Initial funding YY2017-002 sponsored by Guangdong Second Provincial General Hospital, Grant 201707010436, from Guangzhou city scientific and technological research program and research program, Grant 20173024, sponsored by Chinese Traditional Medicine Bureau of Guangdong Province.

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Authors and Affiliations

  1. Department of Neurology, Guangdong Second Provincial General Hospital, Guangzhou, 510317, Guangdong Province, China

    Haike Lu, Xiaoyu Liang, Yingyi Dai, Zhixin Huang, Yumin Ren, Jianguo Lin & Xintong Liu

  2. Department of Pediatrics, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China

    Sanqing Xu

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  1. Haike Lu
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  2. Sanqing Xu
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Correspondence to Jianguo Lin or Xintong Liu.

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This study was approved by the Ethical Review Committee of Guangdong Second Provincial General Hospital. Informed consent of blood donation was given by healthy adult volunteers who had no record of food allergy or sensitization.

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The authors declare that they have no conflict of interest.

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Lu, H., Xu, S., Liang, X. et al. Advanced Glycated End Products Alter Neutrophil Effect on Regulation of CD4+ T Cell Differentiation Through Induction of Myeloperoxidase and Neutrophil Elastase Activities. Inflammation 42, 559–571 (2019). https://doi.org/10.1007/s10753-018-0913-5

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