Alpha-1 Antitrypsin inhibits ATP-mediated release of Interleukin-1β via CD36 and Nicotinic Acetylcholine receptors

  • While interleukin (IL)-1β is a potent pro-inflammatory cytokine involved in host defense, high levels can cause life-threatening sterile inflammation including systemic inflammatory response syndrome. Hence, the control of IL-1β secretion is of outstanding biomedical importance. In response to a first inflammatory stimulus such as lipopolysaccharide, pro-IL-1β is synthesized as a cytoplasmic inactive pro-form. Extracellular ATP originating from injured cells is a prototypical second signal for inflammasome-dependent maturation and release of IL-1β. The human anti-protease alpha-1 antitrypsin (AAT) and IL-1β regulate each other via mechanisms that are only partially understood. Here, we demonstrate that physiological concentrations of AAT efficiently inhibit ATP-induced release of IL-1β from primary human blood mononuclear cells, monocytic U937 cells, and rat lung tissue, whereas ATP-independent IL-1β release is not impaired. Both, native and oxidized AAT are active, suggesting that the inhibition of IL-1β release is independent of the anti-elastase activity of AAT. Signaling of AAT in monocytic cells involves the lipid scavenger receptor CD36, calcium-independent phospholipase A2β, and the release of a small soluble mediator. This mediator leads to the activation of nicotinic acetylcholine receptors, which efficiently inhibit ATP-induced P2X7 receptor activation and inflammasome assembly. We suggest that AAT controls ATP-induced IL-1β release from human mononuclear blood cells by a novel triple-membrane-passing signaling pathway. This pathway may have clinical implications for the prevention of sterile pulmonary and systemic inflammation.

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Author:Kathrin Siebers, Bijan Fink, Anna Zakrzewicz, Alisa Agné, Katrin Richter, Sebastian Konzok, Andreas Hecker, Sven Zukunft, Mira Küllmar, Jochen KleinORCiDGND, J. Michael McIntosh, Thomas Timm, Katherina Sewald, Winfried Padberg, Nupur Aggarwal, Walee Chamulitrat, Sentot Santoso, Wendy Xia, Sabina Janciauskiene, Veronika Grau
Pubmed Id:
Parent Title (English):Frontiers in immunology
Publisher:Frontiers Media
Place of publication:Lausanne
Contributor(s):Soohyun Kim
Document Type:Article
Year of Completion:2018
Date of first Publication:2018/04/25
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/07/19
Tag:CD36; CHRNA10; CHRNA7; CHRNA9; P2X7 receptor; calcium-independent phospholipase A2β; inflammasome; interleukin-1β
Issue:Art. 877
Page Number:15
First Page:1
Last Page:15
Copyright: © 2018 Siebers, Fink, Zakrzewicz, Agné, Richter, Konzok, Hecker, Zukunft, Küllmar, Klein, McIntosh, Timm, Sewald, Padberg, Aggarwal, Chamulitrat, Santoso, Xia, Janciauskiene and Grau. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Institutes:Biochemie, Chemie und Pharmazie / Pharmazie
Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0