Stiftung Tierärztliche Hochschule Hannover (TiHo)

A human antithrombin isoform dampens inflammatory responses and protects from organ damage during bacterial infection

Papareddy, Praveen ORCID; Rossnagel, Madlen; Hollwedel, Femke Doreen ORCID; Kilic, Gülcan; Veerla, Srinivas; Naudin, Clément ORCID; Smeds, Emanuel; Westman, Johannes ORCID; Martinez-Martinez, Irene ORCID; Egesten, Arne; de la Morena-Barrio, Maria Eugenia ORCID; Corral, Javier; Linder, Adam; Artoni, Andrea; Abbattista, Maria; Novembrino, Cristina; Herbert Brakebusch, Cord; Martinelli, Ida; Kasetty, Gopinath; Herwald, Heiko ORCID

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.

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