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Advanced glycation endproducts induce self- and cross-tolerance in monocytes

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Abstract

Introduction

Advanced glycation endproducts (AGEs) are well-known inflammatory mediators, which are recognized by immune cells through their corresponding receptor RAGE and have been shown to participate in the pathophysiology of a variety of acute as well as chronic inflammatory diseases. Nevertheless, no data are available on the aftermath of AGE recognition on immune cells.

Materials and methods

We used the monocytic cell line MonoMac6 as well as primary human monocytes for double stimulation experiments. We measured secreted as well as intracellular levels of TNF-α using ELISA and flow cytometry. In addition, gene expression of surface receptors (RAGE and TLR4) and TNF were measured by qPCR.

Results

Stimulation with AGE leads to a dose-dependent induction of self- and cross-tolerance in both primary monocytes as well as the MonoMac6 cell line. The AGE tolerance depended neither on a decreased expression of RAGE or TLR4, nor on a decrease of TNF-α expression. Nevertheless, intracellular TNF-α was decreased, hinting towards a posttranscriptional regulation.

Conclusion

High levels of AGEs are capable to activate immune cells at first, but induce a secondary state of hypo-responsiveness in these cells. Based on the origin of its causal agent, we propose this phenomenon to be “metabolic tolerance”.

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Author information

Author notes

  1. Florian Uhle and Sebastian Weiterer contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany

    Florian Uhle, Sebastian Weiterer, Benedikt Hermann Siegler, Thorsten Brenner, Christoph Lichtenstern & Markus Alexander Weigand

Author notes

  1. Florian Uhle and Sebastian Weiterer are first authors.

    Authors
    1. Florian Uhle
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    2. Sebastian Weiterer
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    3. Benedikt Hermann Siegler
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    4. Thorsten Brenner
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    5. Christoph Lichtenstern
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    Contributions

    F.U., T.B., C.L., M.A.W.: design and organization of the experiments, performed experiments, data analysis and collection, interpretation of the results and writing of the manuscript. S.W., B.S.: performed sample measurements, interpretation of results and critical revision of the manuscript.

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    Correspondence to Florian Uhle.

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    Conflict of interest

    The authors declare that there is no conflict of interest regarding the publication of this manuscript. The study was not funded.

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    Responsible Editor: Artur Bauhofer.

    Electronic supplementary material

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    11_2017_1076_MOESM1_ESM.tiff

    Supplementary Fig. 1: Dependency of tolerance induction on glycation and RAGE receptor. (A) MM6 cells were primed for 24 h with unmodified BSA, AGE-modified BSA or LPS for 24 h and re-stimulated with the same compounds for additional 24 h. Supernatant TNF-α was assessed by ELISA and graph shows mean ± SEM, n = 3. (B) MM6 cells were primed (or left unprimed) in the presence of RAGE inhibitor 230 nM FPS-ZM1 for 24 h and re-stimulated with AGE for additional 24 h. Supernatant TNF-α was assessed by ELISA and graph shows mean ± SEM, n = 4. *: p ≤ 0.05. (TIFF 325 kb)

    11_2017_1076_MOESM2_ESM.tif

    Supplementary Fig. 2: Impact of LPS- and AGE-tolerance on the production of different cytokines. MM6 cells were primed with increasing doses of either LPS or AGE for 24 h and subsequently re-stimulated with LPS (left column) or AGE-BSA (right column) for further 24 h. Graph shows mean ± SEM, n = 3. (TIFF 5462 kb)

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    Uhle, F., Weiterer, S., Siegler, B.H. et al. Advanced glycation endproducts induce self- and cross-tolerance in monocytes. Inflamm. Res. 66, 961–968 (2017). https://doi.org/10.1007/s00011-017-1076-9

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    • DOI: https://doi.org/10.1007/s00011-017-1076-9

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