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A human antithrombin isoform dampens inflammatory responses and protects from organ damage during bacterial infection.
- Source :
-
Nature microbiology [Nat Microbiol] 2019 Dec; Vol. 4 (12), pp. 2442-2455. Date of Electronic Publication: 2019 Sep 23. - Publication Year :
- 2019
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 2058-5276
- Volume :
- 4
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Nature microbiology
- Publication Type :
- Academic Journal
- Accession number :
- 31548687
- Full Text :
- https://doi.org/10.1038/s41564-019-0559-6