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

Papareddy, Praveen LU ; Rossnagel, Madlen; Doreen Hollwedel, Femke; Kilic, Gülcan; Veerla, Srinivas LU ; Naudin, Clément LU ; Smeds, Emanuel LU ; Westman, Johannes LU ; Martinez-Martinez, Irene and Egesten, Arne LU , et al. (2019) In Nature Microbiology p.1-14
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... (More)

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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@article{80d50f48-317b-42d1-8fcb-26d3df421559,
  abstract     = {<p>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.</p>},
  author       = {Papareddy, Praveen and Rossnagel, Madlen and Doreen Hollwedel, Femke and Kilic, Gülcan and Veerla, Srinivas and Naudin, Clément and Smeds, Emanuel and Westman, Johannes and Martinez-Martinez, Irene and Egesten, Arne and de la Morena-Barrio, Maria Eugenia and Corral, Javier and Linder, Adam and Artoni, Andrea and Abbattista, Maria and Novembrino, Cristina and Herbert Brakebusch, Cord and Martinelli, Ida and Kasetty, Gopinath and Herwald, Heiko},
  issn         = {1740-1534},
  language     = {eng},
  month        = {09},
  pages        = {1--14},
  publisher    = {Nature Publishing Group},
  series       = {Nature Microbiology},
  title        = {A human antithrombin isoform dampens inflammatory responses and protects from organ damage during bacterial infection},
  url          = {http://dx.doi.org/10.1038/s41564-019-0559-6},
  year         = {2019},
}