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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

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

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.

OriginalsprogEngelsk
TidsskriftNature Microbiology
Vol/bind4
Udgave nummer12
Sider (fra-til)2442-2455
Antal sider12
ISSN2058-5276
DOI
StatusUdgivet - dec. 2019

ID: 230149112