Advertisement

Immunologic Research

, Volume 67, Issue 1, pp 77–83 | Cite as

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

  • Zhi-Min Wei
  • Zhuo Wang
  • Xiao-Jian Wan
  • Xian-Jing Li
  • Yi-Xing Li
  • Yang Bai
  • Xue Yang
  • Yong YangEmail author
  • Shun-Chang JiaoEmail author
  • Zhe-Feng LiuEmail author
Original Article
  • 88 Downloads

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.

Keywords

LPS TLR4 FcRγ ERK 

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

Notes

Funding information

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).

Compliance with ethical standards

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.

References

  1. 1.
    Miller SI, Ernst RK, Bader MW. LPS, TLR4 and infectious disease diversity. Nat Rev Microbiol. 2005;3(1):36–46.CrossRefGoogle Scholar
  2. 2.
    Liew FY, Xu D, Brint EK, O'Neill LA. Negative regulation of toll-like receptor-mediated immune responses. Nat Rev Immunol. 2005;5(6):446–58.CrossRefGoogle Scholar
  3. 3.
    Kugelberg E. Pattern recognition receptors: curbing gut inflammation. Nat Rev Immunol. 2014;14(9):583.CrossRefGoogle Scholar
  4. 4.
    Triantafilou M, Triantafilou K. Lipopolysaccharide recognition: CD14, TLRs and the LPS-activation cluster. Trends Immunol. 2002;23(6):301–4.CrossRefGoogle Scholar
  5. 5.
    Pfeiffer A, Bottcher A, Orso E, Kapinsky M, Nagy P, Bodnar A, et al. Lipopolysaccharide and ceramide docking to CD14 provokes ligand-specific receptor clustering in rafts. Eur J Immunol. 2001;31(11):3153–64.CrossRefGoogle Scholar
  6. 6.
    Han C, Jin J, Xu S, Liu H, Li N, Cao X. Integrin CD11b negatively regulates TLR-triggered inflammatory responses by activating Syk and promoting degradation of MyD88 and TRIF via Cbl-b. Nat Immunol. 2010;11(8):734–42.CrossRefGoogle Scholar
  7. 7.
    Zanoni I, Ostuni R, Marek LR, Barresi S, Barbalat R, Barton GM, et al. CD14 controls the LPS-induced endocytosis of toll-like receptor 4. Cell. 2011;147(4):868–80.CrossRefGoogle Scholar
  8. 8.
    Zanoni I, Tan Y, Di Gioia M, Springstead JR, Kagan JC. By capturing inflammatory lipids released from dying cells, the receptor CD14 induces Inflammasome-dependent phagocyte Hyperactivation. Immunity. 2017;47(4):697–709 e3.CrossRefGoogle Scholar
  9. 9.
    Chen Y, Huang W, Yang M, Xin G, Cui W, Xie Z, et al. Cardiotonic steroids stimulate macrophage inflammatory responses through a pathway involving CD36, TLR4, and Na/K-ATPase. Arterioscler Thromb Vasc Biol. 2017;37(8):1462–9.CrossRefGoogle Scholar
  10. 10.
    Zhang X, Kimura Y, Fang C, Zhou L, Sfyroera G, Lambris JD, et al. Regulation of toll-like receptor-mediated inflammatory response by complement in vivo. Blood. 2007;110(1):228–36.CrossRefGoogle Scholar
  11. 11.
    Rittirsch D, Flierl MA, Day DE, Nadeau BA, Zetoune FS, Sarma JV, et al. Cross-talk between TLR4 and FcgammaReceptorIII (CD16) pathways. PLoS Pathog. 2009;5(6):e1000464.CrossRefGoogle Scholar
  12. 12.
    Aleyd E, Heineke MH, van Egmond M. The era of the immunoglobulin a fc receptor FcalphaRI; its function and potential as target in disease. Immunol Rev. 2015;268(1):123–38.CrossRefGoogle Scholar
  13. 13.
    Wakefield DL, Holowka D, Baird B. The FcepsilonRI Signaling Cascade and Integrin Trafficking Converge at Patterned Ligand Surfaces. Mol Bio Cell. 2017; 28(23):3383–96.Google Scholar
  14. 14.
    Li X, Wang D, Chen Z, Lu E, Wang Z, Duan J, et al. Galphai1 and Galphai3 regulate macrophage polarization by forming a complex containing CD14 and Gab1. Proc Natl Acad U S A. 2015;112(15):4731–6.CrossRefGoogle Scholar
  15. 15.
    Voss OH, Murakami Y, Pena MY, Lee HN, Tian L, Margulies DH, et al. Lipopolysaccharide-induced CD300b receptor binding to toll-like receptor 4 alters signaling to drive cytokine responses that enhance septic shock. Immunity. 2016;44(6):1365–78.CrossRefGoogle Scholar
  16. 16.
    Haziot A, Ferrero E, Köntgen F, Hijiya N, Yamamoto S, Silver J, et al. Gram-negative bacteria in CD14-deficient mice. Immunity. 1996;4:407–14.CrossRefGoogle Scholar
  17. 17.
    Li X, Wang Z, Zou Y, Lu E, Duan J, Yang H, et al. Pretreatment with lipopolysaccharide attenuates diethylnitrosamine-caused liver injury in mice via TLR4-dependent induction of Kupffer cell M2 polarization. Immunol Res. 2015;62(2):137–45.CrossRefGoogle Scholar
  18. 18.
    Rosadini CV, Kagan JC. Early innate immune responses to bacterial LPS. Curr Opin Immunol. 2017 Feb;44:14–9.CrossRefGoogle Scholar
  19. 19.
    Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol. 2013;13(12):862–74.CrossRefGoogle Scholar
  20. 20.
    Lucas M, Zhang X, Prasanna V, Mosser DM. ERK activation following macrophage FcgammaR ligation leads to chromatin modifications at the IL-10 locus. J Immunol. 2005;175(1):469–77.CrossRefGoogle Scholar
  21. 21.
    Angus DC, van der Poll T. Severe sepsis and septic shock. New Engl J Med. 2013;369(21):2063.Google Scholar
  22. 22.
    Kang JH, Super M, Yung CW, Cooper RM, Domansky K, Graveline AR, et al. An extracorporeal blood-cleansing device for sepsis therapy. Nat Med. 2014;20(10):1211–6.CrossRefGoogle Scholar
  23. 23.
    Ramachandran G, Kaempfer R, Chung CS, Shirvan A, Chahin AB, Palardy JE, et al. CD28 homodimer interface mimetic peptide acts as a preventive and therapeutic agent in models of severe bacterial sepsis and gram-negative bacterial peritonitis. J Infect Dis. 2015;211(6):995–1003.CrossRefGoogle Scholar
  24. 24.
    Vincent JL, Ramesh MK, Ernest D, LaRosa SP, Pachl J, Aikawa N, et al. A randomized, double-blind, placebo-controlled, phase 2b study to evaluate the safety and efficacy of recombinant human soluble thrombomodulin, ART-123, in patients with sepsis and suspected disseminated intravascular coagulation. Crit Care Med. 2013;41(9):2069–79.CrossRefGoogle Scholar
  25. 25.
    Ivashkiv LB. Cross-regulation of signaling by ITAM-associated receptors. Nat Immunol. 2009;10(4):340–7.CrossRefGoogle Scholar
  26. 26.
    Song DH, Lee JO. Sensing of microbial molecular patterns by toll-like receptors. Immunol Rev. 2012;250(1):216–29.CrossRefGoogle Scholar
  27. 27.
    Chu CL, Yu YL, Shen KY, Lowell CA, Lanier LL, Hamerman JA. Increased TLR responses in dendritic cells lacking the ITAM-containing adapters DAP12 and FcRgamma. Eur J Immunol. 2008;38(1):166–73.CrossRefGoogle Scholar
  28. 28.
    Grazia Cappiello M, Sutterwala FS, Trinchieri G, Mosser DM, Ma X. Suppression of Il-12 transcription in macrophages following fc gamma receptor ligation. J Immunol. 2001;166(7):4498–506.CrossRefGoogle Scholar
  29. 29.
    Rogers NC, Slack EC, Edwards AD, Nolte MA, Schulz O, Schweighoffer E, et al. Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity. 2005;22(4):507–17.CrossRefGoogle Scholar
  30. 30.
    Ravetch J, Aderem A. Phagocytic cells. Immunol Rev. 2007;219:5–7.CrossRefGoogle Scholar
  31. 31.
    Martinsson K, Carlsson L, Kleinau S, Hultman P. The effect of activating and inhibiting fc-receptors on murine mercury-induced autoimmunity. J Autoimmun. 2008 Aug;31(1):22–9.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of OncologyGeneral Hospital of Chinese PLABeijingChina
  2. 2.State Key Laboratory of Natural Medicines, Center for New Drug Safety Evaluation and ResearchChina Pharmaceutical UniversityNanjingChina
  3. 3.School of PharmacyNanjing University of Chinese MedicineNanjingChina
  4. 4.Department of Anesthesiology and Intensive Care Medicine, Changhai HospitalSecond Military Medical UniversityShanghaiChina

Personalised recommendations