A human antithrombin isoform dampens inflammatory responses and protects from organ damage during bacterial infection
(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.
(Less)
- author
- organization
-
- Host parasite interactions (research group)
- Infection Medicine (BMC)
- Breastcancer-genetics
- Redox Medicine (research group)
- Antioxidation medicine (research group)
- Respiratory Medicine, Allergology, and Palliative Medicine
- SEBRA Sepsis and Bacterial Resistance Alliance (research group)
- Translational Sepsis research (research group)
- publishing date
- 2019-09-23
- 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
- 2024-09-04 10:33:15
@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}}, }