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FcRγ deficiency improves survival in experimental sepsis by down-regulating TLR4 signaling pathway

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Abstract

Fc receptor common γ signaling chain (FcRγ), a common subunit shared by Fc receptors (FcγRI, III, IV, FcαRI, and FcεRI), is an important immune regulator both in innate and adaptive immunity. Previous studies have shown that FcRγ was a potential target of inflammatory diseases, whereas the role of FcRγ in sepsis has been poorly understood. In this study, we found that deficiency of FcRγ resulted in increased survival in lipopolysaccharide (LPS)/D-galactosamine and E. coli-induced sepsis in mice. This protective effect was characterized by decreased TNF-α, IL-6, and IL-10. Further experiments in bone marrow-derived macrophages (BMDMs) in vitro also showed that FcRγ deficiency resulted in decreased production of TNF-α, IL-6, and IL-10 upon LPS stimulation. The mechanism study showed that FcRγ was physiologically associated with toll-like receptor 4 (TLR4), and tyrosine phosphorylation of FcRγ mediated TLR4 signaling pathway, followed by increased ERK phosphorylation upon LPS stimulation. Our results suggest that FcRγ might be a potential therapeutic target of sepsis.

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Abbreviations

FcRγ:

Fc receptor common γ signaling chain

TLR4:

Toll-like receptor 4

LPS:

Lipopolysaccharide

PAMP:

Pathogen-associated molecule patterns

IFNs:

Interferons

D-gal:

D-galactosamine

BMDMs:

Bone marrow-derived macrophages

ITAM:

Immunoreceptor tyrosine-based activation motif

Syk:

Spleen tyrosine kinase

PLCγ:

Phospholipase C-γ

TNF-α:

Tumor necrosis factor α

IL-6:

Interleukin 6

IL-10:

Interleukin 10

p-Tyr:

Phosphorylation of tyrosine

Tyr:

Tyrosine

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Funding

This work was supported in part by the National Science Foundation of China (Nos. 91529304, 81473230, and 81673468) and the Natural Science Foundation of Jiangsu Province (No. BK20170732).

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Author notes

  1. Zhi-Min Wei and Zhuo Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Oncology, General Hospital of Chinese PLA, 28 Fuxing Road, Beijing, 100853, China

    Zhi-Min Wei, Shun-Chang Jiao & Zhe-Feng Liu

  2. State Key Laboratory of Natural Medicines, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, 211198, China

    Zhuo Wang, Xian-Jing Li, Yi-Xing Li, Yang Bai, Xue Yang & Yong Yang

  3. School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Zhuo Wang

  4. Department of Anesthesiology and Intensive Care Medicine, Changhai Hospital, Second Military Medical University, 800 Xiangyin Rd, Yangpu Qu, Shanghai, China

    Xiao-Jian Wan

Authors
  1. Zhi-Min Wei
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  2. Zhuo Wang
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  3. Xiao-Jian Wan
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  4. Xian-Jing Li
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  5. Yi-Xing Li
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  6. Yang Bai
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  7. Xue Yang
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  8. Yong Yang
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  9. Shun-Chang Jiao
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  10. Zhe-Feng Liu
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Corresponding authors

Correspondence to Yong Yang, Shun-Chang Jiao or Zhe-Feng Liu.

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All animal experiments were performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Center for New Drug Evaluation and Research, China Pharmaceutical University, Nanjing, China.

Conflict of interest

The authors declare that they have no conflict of interest.

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Wei, ZM., Wang, Z., Wan, XJ. et al. FcRγ deficiency improves survival in experimental sepsis by down-regulating TLR4 signaling pathway. Immunol Res 67, 77–83 (2019). https://doi.org/10.1007/s12026-018-9039-y

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  • DOI: https://doi.org/10.1007/s12026-018-9039-y

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