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Alpha-1 antitrypsin inhibits ATP-mediated release of interleukin-1β via CD36 and nicotinic acetylcholine receptors

: Siebers, Kathrin; Fink, Bijan; Zakrzewicz, Anna; Agné, Alisa; Richter, Katrin; Konzok, Sebastian; Hecker, Andreas; Zukunft, Sven; Küllmar, Mira; Klein, Jochen; McIntosh, J. Michael; Timm, Thomas; Sewald, Katherina; Padberg, Winfried; Aggarwal, Nupur; Chamulitrat, Walee; Santoso, Sentot; Xia, Wendy; Janciauskiene, Sabina; Grau, Veronika

Fulltext urn:nbn:de:0011-n-5099248 (1.7 MByte PDF)
MD5 Fingerprint: a3d31049c8494ed84c21af799e6909bd
Created on: 18.9.2018

Frontiers in Immunology 9 (2018), Art. 877, 15 pp.
ISSN: 1664-3224 (online)
Journal Article, Electronic Publication
Fraunhofer ITEM ()
Cd36; Chrna10; Chrna7; Chrna9; P2X7 receptor; calcium-independent phospholipase A2beta; inflammasome; Interleukin-1beta

While interleukin (IL)-1beta 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-1beta secretion is of outstanding biomedical importance. In response to a first inflammatory stimulus such as lipopolysaccharide, pro-IL-1beta 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-1beta. The human anti-protease alpha-1 antitrypsin (AAT) and IL-1beta 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-1beta from primary human blood mononuclear cells, monocytic U937 cells, and rat lung tissue, whereas ATP-independent IL-1beta release is not impaired. Both, native and oxidized AAT are active, suggesting that the inhibition of IL-1beta 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 A2beta, 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-1beta 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.