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Autoinhibitory regu...
Autoinhibitory regulation of S100A8/S100A9 alarmin activity locally restricts sterile inflammation
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- Vogl, Thomas (author)
- University Hospital Münster,University of Münster
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- Stratis, Athanasios (author)
- University Hospital Münster
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- Wixler, Viktor (author)
- University Hospital Münster
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- Völler, Tom (author)
- University of Münster
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- Thurainayagam, Sumita (author)
- University of Münster
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- Jorch, Selina K. (author)
- University of Münster
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- Zenker, Stefanie (author)
- University of Münster
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- Dreiling, Alena (author)
- University of Münster
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- Chakraborty, Deblina (author)
- University of Münster
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- Fröhling, Mareike (author)
- University Hospital Münster
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- Paruzel, Peter (author)
- University Hospital Münster
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- Wehmeyer, Corinna (author)
- University Hospital Münster
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- Hermann, Sven (author)
- University of Münster
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- Papantonopoulou, Olympia (author)
- University of Bonn
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- Geyer, Christiane (author)
- University of Münster
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- Loser, Karin (author)
- University of Münster
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- Schäfers, Michael (author)
- University of Münster
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- Ludwig, Stephan (author)
- University of Münster,University Hospital Münster
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- Stoll, Monika (author)
- University of Münster
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- Leanderson, Tomas (author)
- Lund University,Lunds universitet,Immunologi,Forskargrupper vid Lunds universitet,Immunology,Lund University Research Groups
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- Schultze, Joachim L. (author)
- University of Bonn
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- König, Simone (author)
- University of Münster
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- Pap, Thomas (author)
- University Hospital Münster
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- Roth, Johannes (author)
- University of Münster
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(creator_code:org_t)
- 2018
- 2018
- English 15 s.
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In: Journal of Clinical Investigation. - 0021-9738. ; 128:5, s. 1852-1866
- Related links:
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http://dx.doi.org/10...
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Reumatologi och inflammation (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Rheumatology and Autoimmunity (hsv//eng)
Publication and Content Type
- art (subject category)
- ref (subject category)
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- By the author/editor
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Vogl, Thomas
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Stratis, Athanas ...
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Wixler, Viktor
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Völler, Tom
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Thurainayagam, S ...
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Jorch, Selina K.
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show more...
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Zenker, Stefanie
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Dreiling, Alena
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Chakraborty, Deb ...
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Fröhling, Mareik ...
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Paruzel, Peter
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Wehmeyer, Corinn ...
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Hermann, Sven
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Papantonopoulou, ...
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Geyer, Christian ...
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Loser, Karin
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Schäfers, Michae ...
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Ludwig, Stephan
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Stoll, Monika
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Leanderson, Toma ...
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Schultze, Joachi ...
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König, Simone
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Pap, Thomas
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Roth, Johannes
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Rheumatology and ...
- Articles in the publication
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Journal of Clini ...
- By the university
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Lund University