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Autoinhibitory regulation of S100A8/S100A9 alarmin activity locally restricts sterile inflammation

Vogl, Thomas; Stratis, Athanasios; Wixler, Viktor; Völler, Tom; Thurainayagam, Sumita; Jorch, Selina K.; Zenker, Stefanie; Dreiling, Alena; Chakraborty, Deblina and Fröhling, Mareike, et al. (2018) In Journal of Clinical Investigation 128(5). p.1852-1866
Abstract

Autoimmune diseases, such as psoriasis and arthritis, show a patchy distribution of inflammation despite systemic dysregulation of adaptive immunity. Thus, additional tissue-derived signals, such as danger-associated molecular patterns (DAMPs), are indispensable for manifestation of local inflammation. S100A8/S100A9 complexes are the most abundant DAMPs in many autoimmune diseases. However, regulatory mechanisms locally restricting DAMP activities are barely understood. We now unravel for the first time, to our knowledge, a mechanism of autoinhibition in mice and humans restricting S100-DAMP activity to local sites of inflammation. Combining protease degradation, pull-down assays, mass spectrometry, and targeted mutations, we identified... (More)

Autoimmune diseases, such as psoriasis and arthritis, show a patchy distribution of inflammation despite systemic dysregulation of adaptive immunity. Thus, additional tissue-derived signals, such as danger-associated molecular patterns (DAMPs), are indispensable for manifestation of local inflammation. S100A8/S100A9 complexes are the most abundant DAMPs in many autoimmune diseases. However, regulatory mechanisms locally restricting DAMP activities are barely understood. We now unravel for the first time, to our knowledge, a mechanism of autoinhibition in mice and humans restricting S100-DAMP activity to local sites of inflammation. Combining protease degradation, pull-down assays, mass spectrometry, and targeted mutations, we identified specific peptide sequences within the second calcium-binding EF-hands triggering TLR4/MD2-dependent inflammation. These binding sites are free when S100A8/S100A9 heterodimers are released at sites of inflammation. Subsequently, S100A8/S100A9 activities are locally restricted by calcium-induced (S100A8/ S100A9)2 tetramer formation hiding the TLR4/MD2-binding site within the tetramer interphase, thus preventing undesirable systemic effects. Loss of this autoinhibitory mechanism in vivo results in TNF-α-driven fatal inflammation, as shown by lack of tetramer formation in crossing S100A9-/- mice with 2 independent TNF-α-transgene mouse strains. Since S100A8/S100A9 is the most abundant DAMP in many inflammatory diseases, specifically blocking the TLR4-binding site of active S100 dimers may represent a promising approach for local suppression of inflammatory diseases, avoiding systemic side effects.

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Journal of Clinical Investigation
volume
128
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5
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15 pages
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The Journal of Clinical Investigation
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  • scopus:85046407531
ISSN
0021-9738
DOI
10.1172/JCI89867
language
English
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yes
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510b78f7-8cfb-4345-957d-d9c930b0a9b8
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2018-05-15 14:28:55
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2018-05-16 03:00:03
@article{510b78f7-8cfb-4345-957d-d9c930b0a9b8,
  abstract     = {<p>Autoimmune diseases, such as psoriasis and arthritis, show a patchy distribution of inflammation despite systemic dysregulation of adaptive immunity. Thus, additional tissue-derived signals, such as danger-associated molecular patterns (DAMPs), are indispensable for manifestation of local inflammation. S100A8/S100A9 complexes are the most abundant DAMPs in many autoimmune diseases. However, regulatory mechanisms locally restricting DAMP activities are barely understood. We now unravel for the first time, to our knowledge, a mechanism of autoinhibition in mice and humans restricting S100-DAMP activity to local sites of inflammation. Combining protease degradation, pull-down assays, mass spectrometry, and targeted mutations, we identified specific peptide sequences within the second calcium-binding EF-hands triggering TLR4/MD2-dependent inflammation. These binding sites are free when S100A8/S100A9 heterodimers are released at sites of inflammation. Subsequently, S100A8/S100A9 activities are locally restricted by calcium-induced (S100A8/ S100A9)<sub>2</sub> tetramer formation hiding the TLR4/MD2-binding site within the tetramer interphase, thus preventing undesirable systemic effects. Loss of this autoinhibitory mechanism in vivo results in TNF-α-driven fatal inflammation, as shown by lack of tetramer formation in crossing S100A9<sup>-/-</sup> mice with 2 independent TNF-α-transgene mouse strains. Since S100A8/S100A9 is the most abundant DAMP in many inflammatory diseases, specifically blocking the TLR4-binding site of active S100 dimers may represent a promising approach for local suppression of inflammatory diseases, avoiding systemic side effects.</p>},
  author       = {Vogl, Thomas and Stratis, Athanasios and Wixler, Viktor and Völler, Tom and Thurainayagam, Sumita and Jorch, Selina K. and Zenker, Stefanie and Dreiling, Alena and Chakraborty, Deblina and Fröhling, Mareike and Paruzel, Peter and Wehmeyer, Corinna and Hermann, Sven and Papantonopoulou, Olympia and Geyer, Christiane and Loser, Karin and Schäfers, Michael and Ludwig, Stephan and Stoll, Monika and Leanderson, Tomas and Schultze, Joachim L. and König, Simone and Pap, Thomas and Roth, Johannes},
  issn         = {0021-9738},
  language     = {eng},
  month        = {05},
  number       = {5},
  pages        = {1852--1866},
  publisher    = {The Journal of Clinical Investigation},
  series       = {Journal of Clinical Investigation},
  title        = {Autoinhibitory regulation of S100A8/S100A9 alarmin activity locally restricts sterile inflammation},
  url          = {http://dx.doi.org/10.1172/JCI89867},
  volume       = {128},
  year         = {2018},
}