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

Papareddy, Praveen LU orcid ; Rossnagel, Madlen ; Doreen Hollwedel, Femke ; Kilic, Gülcan ; Veerla, Srinivas LU orcid ; Naudin, Clément LU ; Smeds, Emanuel LU ; Westman, Johannes LU ; Martinez-Martinez, Irene and Egesten, Arne LU , et al. (2019) In Nature Microbiology 4(12). p.2442-2455
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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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Microbiology
volume
4
issue
12
pages
2442 - 2455
publisher
Springer Nature
external identifiers
  • scopus:85074049504
  • pmid:31548687
ISSN
2058-5276
DOI
10.1038/s41564-019-0559-6
language
English
LU publication?
yes
id
80d50f48-317b-42d1-8fcb-26d3df421559
date added to LUP
2019-10-08 13:04:26
date last changed
2024-04-02 17:37:55
@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         = {{2058-5276}},
  language     = {{eng}},
  month        = {{09}},
  number       = {{12}},
  pages        = {{2442--2455}},
  publisher    = {{Springer Nature}},
  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}},
  doi          = {{10.1038/s41564-019-0559-6}},
  volume       = {{4}},
  year         = {{2019}},
}