1. A human antithrombin isoform dampens inflammatory responses and protects from organ damage during bacterial infection.
- Author
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Papareddy P, Rossnagel M, Doreen Hollwedel F, Kilic G, Veerla S, Naudin C, Smeds E, Westman J, Martinez-Martinez I, Egesten A, de la Morena-Barrio ME, Corral J, Linder A, Artoni A, Abbattista M, Novembrino C, Herbert Brakebusch C, Martinelli I, Kasetty G, and Herwald H
- Subjects
- Animals, Antithrombins blood, Chemokines, Cytokines, Disease Models, Animal, Escherichia coli immunology, Escherichia coli Infections microbiology, Humans, Lipopolysaccharides adverse effects, Male, Mice, Mice, Transgenic, Monocytes, Mutation, NF-kappa B, Protein Isoforms, RAW 264.7 Cells, Antithrombins chemistry, Antithrombins immunology, Bacterial Infections immunology
- Abstract
Severe infectious diseases are often characterized by an overwhelming and unbalanced systemic immune response to microbial infections. Human antithrombin (hAT) is a crucial coagulation inhibitor with anti-inflammatory activities. Here we identify three hAT-binding proteins (CD13, CD300f and LRP-1) on human monocytes that are involved in blocking the activity of nuclear factor-κB. We found that the modulating effect is primarily restricted to the less abundant β-isoform (hβAT) of hAT that lacks N-glycosylation at position 135. Individuals with a mutation at this position have increased production of hβAT and analysis of their blood, which was stimulated ex vivo with lipopolysaccharide, showed a decreased inflammatory response. Similar findings were recorded when heterozygotic mice expressing hAT or hβAT were challenged with lipopolysaccharide or infected with Escherichia coli bacteria. Our results finally demonstrate that in a lethal E. coli infection model, survival rates increased when mice were treated with hβAT one hour and five hours after infection. The treatment also resulted in a reduction of the inflammatory response and less severe organ damage.
- Published
- 2019
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