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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.

Authors+Show Affiliations

Division of Infection Medicine, Lund, Department of Clinical Sciences, Lund University, Lund, Sweden.Division of Infection Medicine, Lund, Department of Clinical Sciences, Lund University, Lund, Sweden.Division of Infection Medicine, Lund, Department of Clinical Sciences, Lund University, Lund, Sweden. Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Hannover, Germany.Biotech Research and Innovation Center, University of Copenhagen, Copenhagen, Denmark.Division of Oncology and Pathology, Lund, Department of Clinical Sciences, Lund University, Lund, Sweden.Division of Infection Medicine, Lund, Department of Clinical Sciences, Lund University, Lund, Sweden.Division of Infection Medicine, Lund, Department of Clinical Sciences, Lund University, Lund, Sweden.Division of Infection Medicine, Lund, Department of Clinical Sciences, Lund University, Lund, Sweden. Program in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, IMIB-Arrixaca, CIBERER, Universidad de Murcia, Murcia, Spain.Division of Respiratory Medicine and Allergology, Lund, Department of Clinical Sciences, Lund University, Lund, Sweden.Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, IMIB-Arrixaca, CIBERER, Universidad de Murcia, Murcia, Spain.Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, IMIB-Arrixaca, CIBERER, Universidad de Murcia, Murcia, Spain.Division of Infection Medicine, Lund, Department of Clinical Sciences, Lund University, Lund, Sweden.Angelo Bianchi Bonomi Haemophilia and Thrombosis Centre, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy.Angelo Bianchi Bonomi Haemophilia and Thrombosis Centre, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy.Angelo Bianchi Bonomi Haemophilia and Thrombosis Centre, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy.Biotech Research and Innovation Center, University of Copenhagen, Copenhagen, Denmark.Angelo Bianchi Bonomi Haemophilia and Thrombosis Centre, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy.Division of Respiratory Medicine and Allergology, Lund, Department of Clinical Sciences, Lund University, Lund, Sweden. Institute of Biomedicine, Department of Microbiology and Immunology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.Division of Infection Medicine, Lund, Department of Clinical Sciences, Lund University, Lund, Sweden. heiko.hewald@med.lu.se.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31548687

Citation

Papareddy, Praveen, et al. "A Human Antithrombin Isoform Dampens Inflammatory Responses and Protects From Organ Damage During Bacterial Infection." Nature Microbiology, 2019.
Papareddy P, Rossnagel M, Doreen Hollwedel F, et al. A human antithrombin isoform dampens inflammatory responses and protects from organ damage during bacterial infection. Nat Microbiol. 2019.
Papareddy, P., Rossnagel, M., Doreen Hollwedel, F., Kilic, G., Veerla, S., Naudin, C., ... Herwald, H. (2019). A human antithrombin isoform dampens inflammatory responses and protects from organ damage during bacterial infection. Nature Microbiology, doi:10.1038/s41564-019-0559-6.
Papareddy P, et al. A Human Antithrombin Isoform Dampens Inflammatory Responses and Protects From Organ Damage During Bacterial Infection. Nat Microbiol. 2019 Sep 23; PubMed PMID: 31548687.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A human antithrombin isoform dampens inflammatory responses and protects from organ damage during bacterial infection. 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, Y1 - 2019/09/23/ PY - 2019/03/25/received PY - 2019/08/08/accepted PY - 2019/9/25/entrez JF - Nature microbiology JO - Nat Microbiol 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. SN - 2058-5276 UR - https://www.unboundmedicine.com/medline/citation/31548687/A_human_antithrombin_isoform_dampens_inflammatory_responses_and_protects_from_organ_damage_during_bacterial_infection L2 - http://dx.doi.org/10.1038/s41564-019-0559-6 DB - PRIME DP - Unbound Medicine ER -