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

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; Cord Herbert Brakebusch; Ida Martinelli; Gopinath Kasetty; Heiko Herwald

doi:10.1038/s41564-019-0559-6

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

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, Cord Herbert Brakebusch, Ida Martinelli, Gopinath Kasetty, Heiko Herwald^*

^*Corresponding author for this work

7 Citations (Scopus)

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 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.

Original language	English
Journal	Nature Microbiology
Volume	4
Issue number	12
Pages (from-to)	2442-2455
Number of pages	12
ISSN	2058-5276
DOIs	https://doi.org/10.1038/s41564-019-0559-6
Publication status	Published - 1 Dec 2019

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Papareddy, P., Rossnagel, M., Doreen Hollwedel, F., Kilic, G., Veerla, S., Naudin, C., Smeds, E., Westman, J., Martinez-Martinez, I., Egesten, A., de la Morena-Barrio, M. E., Corral, J., Linder, A., Artoni, A., Abbattista, M., Novembrino, C., Herbert Brakebusch, C., Martinelli, I., Kasetty, G., & Herwald, H. (2019). A human antithrombin isoform dampens inflammatory responses and protects from organ damage during bacterial infection. Nature Microbiology, 4(12), 2442-2455. https://doi.org/10.1038/s41564-019-0559-6

Papareddy, P, Rossnagel, M, Doreen Hollwedel, F, Kilic, G, Veerla, S, Naudin, C, Smeds, E, Westman, J, Martinez-Martinez, I, Egesten, A, de la Morena-Barrio, ME, Corral, J, Linder, A, Artoni, A, Abbattista, M, Novembrino, C, Herbert Brakebusch, C, Martinelli, I, Kasetty, G & Herwald, H 2019, 'A human antithrombin isoform dampens inflammatory responses and protects from organ damage during bacterial infection', Nature Microbiology, vol. 4, no. 12, pp. 2442-2455. https://doi.org/10.1038/s41564-019-0559-6

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title = "A human antithrombin isoform dampens inflammatory responses and protects from organ damage during bacterial infection",

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 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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AU - Papareddy, Praveen

AU - Rossnagel, Madlen

AU - Doreen Hollwedel, Femke

AU - Kilic, Gülcan

AU - Veerla, Srinivas

AU - Naudin, Clément

AU - Smeds, Emanuel

AU - Westman, Johannes

AU - Martinez-Martinez, Irene

AU - Egesten, Arne

AU - de la Morena-Barrio, Maria Eugenia

AU - Corral, Javier

AU - Linder, Adam

AU - Artoni, Andrea

AU - Abbattista, Maria

AU - Novembrino, Cristina

AU - Herbert Brakebusch, Cord

AU - Martinelli, Ida

AU - Kasetty, Gopinath

AU - Herwald, Heiko

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

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

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