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

Research output: Contribution to journalArticle


title = "Autoinhibitory regulation of S100A8/S100A9 alarmin activity locally restricts sterile inflammation",
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 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.",
author = "Thomas Vogl and Athanasios Stratis and Viktor Wixler and Tom V{\"o}ller and Sumita Thurainayagam and Jorch, {Selina K.} and Stefanie Zenker and Alena Dreiling and Deblina Chakraborty and Mareike Fr{\"o}hling and Peter Paruzel and Corinna Wehmeyer and Sven Hermann and Olympia Papantonopoulou and Christiane Geyer and Karin Loser and Michael Sch{\"a}fers and Stephan Ludwig and Monika Stoll and Tomas Leanderson and Schultze, {Joachim L.} and Simone K{\"o}nig and Thomas Pap and Johannes Roth",
year = "2018",
month = "5",
day = "1",
doi = "10.1172/JCI89867",
language = "English",
volume = "128",
pages = "1852--1866",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "Am Soc Clin Investig",
number = "5",