Journal
FRONTIERS IN IMMUNOLOGY
Volume 9, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2018.00877
Keywords
CD36; CHRNA 7; CHRNA 9; CHRNA 10; inflammasome; interleukin-1 beta; calcium-independent phospholipase A2 beta; P2X7 receptor
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Funding
- LOEWE Program of the State of Hesse (Non-neuronal cholinergic systems)
- German Centre for Lung Research
- Excellence Cluster Cardio-Pulmonary Systems
- German Research Foundation [GR 1094/7-1]
- National Institutes of Health [GM48677, GM103801]
- Guangdong Science Foundation [2016A030313123]
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While interleukin (IL)-1 beta 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-1 beta secretion is of outstanding biomedical importance. In response to a first inflammatory stimulus such as lipopolysaccharide, pro-IL-1 beta 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-1 beta. The human anti-protease alpha-1 antitrypsin (AAT) and IL-1 beta 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-1 beta from primary human blood mononuclear cells, monocytic U937 cells, and rat lung tissue, whereas ATP-independent IL-1 beta release is not impaired. Both, native and oxidized AAT are active, suggesting that the inhibition of IL-1 beta 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 A2 beta, 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-1 beta 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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