A human antithrombin isoform dampens inflammatory responses and protects from organ damage during bacterial infection
Research output: Contribution to journal › Journal article › Research › peer-review
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.
Original language | English |
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Journal | Nature Microbiology |
Volume | 4 |
Issue number | 12 |
Pages (from-to) | 2442-2455 |
Number of pages | 12 |
ISSN | 2058-5276 |
DOIs | |
Publication status | Published - 2019 |
ID: 230149112