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Open AccessArticle

Amyloid Beta Peptide (Aβ1-42) Reverses the Cholinergic Control of Monocytic IL-1β Release

1
Department of General and Thoracic Surgery, Laboratory of Experimental Surgery, Justus-Liebig-University Giessen, German Center for Lung Research, 35392 Giessen, Germany
2
Department of Internal Medicine, Justus-Liebig-University Giessen, 35392 Giessen, Germany
3
Physiological Institute, Justus-Liebig-University Giessen, 35392 Giessen, Germany
4
Department of Animal Physiology and Molecular Biomedicine, Justus-Liebig-University Giessen, 35392 Giessen, Germany
5
Institute of Pharmacology and Toxicology, RWTH Aachen University, 52074 Aachen, Germany
6
Department of Biology, University of Utah, Salt Lake City, UT 84112, USA
7
George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, UT 84148, USA
8
Department of Psychiatry, University of Utah, Salt Lake City, UT 84108, USA
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
J. Clin. Med. 2020, 9(9), 2887; https://doi.org/10.3390/jcm9092887
Received: 14 July 2020 / Revised: 1 September 2020 / Accepted: 3 September 2020 / Published: 7 September 2020
(This article belongs to the Special Issue Sepsis: Current Clinical Practices and New Perspectives)
Amyloid-β peptide (Aβ1-42), the cleavage product of the evolutionary highly conserved amyloid precursor protein, presumably plays a pathogenic role in Alzheimer’s disease. Aβ1-42 can induce the secretion of the pro-inflammatory cytokine intereukin-1β (IL-1β) in immune cells within and out of the nervous system. Known interaction partners of Aβ1-42 are α7 nicotinic acetylcholine receptors (nAChRs). The physiological functions of Aβ1-42 are, however, not fully understood. Recently, we identified a cholinergic mechanism that controls monocytic release of IL-1β by canonical and non-canonical agonists of nAChRs containing subunits α7, α9, and/or α10. Here, we tested the hypothesis that Aβ1-42 modulates this inhibitory cholinergic mechanism. Lipopolysaccharide-primed monocytic U937 cells and human mononuclear leukocytes were stimulated with the P2X7 receptor agonist 2′(3′)-O-(4-benzoylbenzoyl)adenosine-5′-triphosphate triethylammonium salt (BzATP) in the presence or absence of nAChR agonists and Aβ1-42. IL-1β concentrations were measured in the supernatant. Aβ1-42 dose-dependently (IC50 = 2.54 µM) reversed the inhibitory effect of canonical and non-canonical nicotinic agonists on BzATP-mediated IL-1β-release by monocytic cells, whereas reverse Aβ42-1 was ineffective. In conclusion, we discovered a novel pro-inflammatory Aβ1-42 function that enables monocytic IL-1β release in the presence of nAChR agonists. These findings provide evidence for a novel physiological function of Aβ1-42 in the context of sterile systemic inflammation. View Full-Text
Keywords: amyloid beta peptide; interleukin-1β; nicotinic acetylcholine receptors; monocytes; systemic inflammation; purinergic signaling; P2X7 receptor; adenosine triphosphate amyloid beta peptide; interleukin-1β; nicotinic acetylcholine receptors; monocytes; systemic inflammation; purinergic signaling; P2X7 receptor; adenosine triphosphate
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Richter, K.; Ogiemwonyi-Schaefer, R.; Wilker, S.; Chaveiro, A.I.; Agné, A.; Hecker, M.; Reichert, M.; Amati, A.-L.; Schlüter, K.-D.; Manzini, I.; Schmalzing, G.; McIntosh, J.M.; Padberg, W.; Grau, V.; Hecker, A. Amyloid Beta Peptide (Aβ1-42) Reverses the Cholinergic Control of Monocytic IL-1β Release. J. Clin. Med. 2020, 9, 2887.

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