ArticleThe Journal of clinical investigation2018
Autoinhibitory regulation of S100A8/S100A9 alarmin activity locally restricts sterile inflammation.
Article in The Journal of clinical investigation, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 133 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
133 citing papers in PubMed, 224 citations in OpenAlex.
- DAMPs, PAMPs, and Alarmins: From Mechanism to Therapy.MedComm · 2026Review
- S100 signaling in hair follicle biology: emerging mechanistic insights and therapeutic opportunities.Journal of molecular histology · 2026Review
- Secreted protein combination GAPDH/S100A8/S100A9 from human expanded potential stem cells counteracts mesenchymal stromal cell senescence.Stem cell research & therapy · 2026Article
- Formation of the intradimer disulfide bond in human calprotectin maintains metal-withholding function and tunes proteolytic susceptibility.Chemical science · 2026Article
- Activation of unfolded protein response pathways promotes keratinocyte differentiation and ameliorates psoriasis phenotypes.Cell stress & chaperones · 2026Article
- Early Proteomic Alterations in Non-segmental Vitiligo Skin Following Treatment with Topical Tacrolimus.Dermatology and therapy · 2026Article
- Inducing bacterial calcification for systematic treatment and immunomodulation against methicillin-resistant Staphylococcus aureus.Nature biotechnology · 2026Article
- Redundant and distinct mechanisms suppress innate immune activation during SARS-CoV-2 infection.PLoS biology · 2026Article
- Fecal Detection of Calprotectin Subunits Links Inflammatory Bowel Disease Activity With Chronicity of Intestinal Inflammation.Gastroenterology · 2026Article
- Succinate receptor 1 restricts hematopoiesis and prevents acute myeloid leukemia progression.Nature communications · 2026Article
- Article
- Chromatin Accessibility Profiling of Keratinocytes from Clinically Healed Psoriatic Skin Reveals Epigenetic Alterations.JID innovations : skin science from molecules to population health · 2026Article
- Article
- Design and characterization of calprotectin tetramerization variants for probing the role of oligomerization in receptor activation.Protein science : a publication of the Protein Society · 2026Article
- CCR1Frontiers in immunology · 2026Article
- A feedback loop sustaining neutrophil extracellular trap formation involves S100 proteins, histones, TLR2 and RAGE, and is restrained by albumin.Frontiers in immunology · 2026Article
- Cytosolic proliferating cell nuclear antigen (PCNA) orchestrates neutrophil hyperactivation in COVID-19.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- From Cytokines to Biomarkers: Mapping the Immunopathology of Inflammatory Bowel Disease.Cells · 2025Review
- Chronic skin and systemic inflammation modulated by S100A8 and S100A9 complexes.Cell death and differentiation · 2025Article
- hPDLSC-ApoEVs attenuate periodontitis and enhance bone regeneration via NF-κB/S100A9-Mediated M2 macrophage polarization.Stem cell research & therapy · 2025Article
73 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
24 authors at 7 institutions in 5 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.