Scientist s of the DZL sites at the Laboratory of Experimental Surgery and Institute of Anatomy and Cell Biology (both Giessen, UGMLC), the Department of Respiratory Medicine and Fraunhofer Institute for Toxicology and Experimental Medicine (both BREATH, Hannover) and the Institute of Medical Biometry and Statistics (ARCN, Lübeck), have recently described a novel anti-inflammatory mechanism of high clinical relevance.

Interleukin-1β (IL-1β) is a potent pro-inflammatory cytokine of innate immunity that can be released in response to extracellular ATP, primarily an endogenous alarm signal of damaged cells. Cell damage is typically caused by accidents, major surgery or extracorporeal circulation. A vital function of IL-1β in traumatized patients is host defense against infections. However, excessively high systemic levels of IL-1β can lead to life-threatening systemic inflammation and death from multi-organ damage. Three years ago, the Laboratory of Experimental Surgery headed by Prof. Dr. Veronika Grau, discovered that stimulation of acetylcholine receptors on human blood monocytes, a type of leukocyte, efficiently inhibits the ATP-mediated release of IL-1β. In this context a whole range of endogenous previously unknown unconventional acetylcholine receptor agonists was discovered. All of these agonists share a phosphocholine head-group.

DZL scientist discovered that the cholinergic control of monocytic IL-1β release is also activated by two well-known acute phase proteins, C-reactive protein (1) and α1-antitrypsin (2). C-reactive protein, is measured innumerable times in daily clinical routine but its actual biological function is poorly understood. Native human C-reactive protein, a pentamer binding one phosphocholine per monomer, turned out to be a strong acetylcholine receptor agonist. By potentiating the effect of endogenously available phosphocholine, C-reactive protein limits IL-1β release, thus, preventing inflammation (1). The mechanism by which the anti-protease α1-antitrypsin eventually activates monocytic acetylcholine receptors is more complicated (2). DZL scientists provided evidence that α1-antitrypsin does not directly activate this receptor. Instead, it binds to the cell surface receptor CD36 on monocytes, which ultimately leads to the secretion of low molecular weight factors that function as acetylcholine receptor agonists in monocytic cells. A similar signaling pathway is also induced by β-nicotinamide adenine dinucleotide, another cytoplasmic molecule that is released by injured cells together with ATP (3).

Interestingly, the endogenous cholinergic control of IL-1β release is hijacked by several human pathogens that decorate their cell surfaces with phosphocholine-modified molecules as an immune evasion strategy, among them Haemophilus influenzae (4). This observation underlines the biological relevance of this newly discovered anti-inflammatory mechanism.

These new insights may pave the way towards the development of new therapies preventing systemic inflammation caused by all kinds of traumatizing medical treatments, including organ transplantation and extracorporeal membrane oxygenation as well as to the development of host-centered anti-microbial therapies.

References:
1. Richter K, Sagawe S, Hecker A, Küllmar M, Askevold I, Damm J, Heldmann S, Pöhlmann M, Ruhrmann S, Sander M, Schlüter K-D, Wilker S, König IR, Kummer W, Padberg W, Hone AJ, McIntosh JM, Zakrzewicz AT, Koch C, Grau V (2018) C-Reactive protein stimulates nicotinic acetylcholine receptors to control ATP-mediated monocytic inflammasome activation. Front Immunol 9: 1604, doi: 10.3389/fimmu.2018.01604
2. Siebers K, Fink B, Zakrzewicz A, Agné A, Richter K, Konzok S, Hecker A, Zukunft S, Küllmar M, Klein J, McIntosh JM, Timm T, Sewald K, Padberg W, Aggarwal N, Chamulitrat W, Santoso S, Xia W, Janciauskiene S, Grau V (2018) Alpha-1 antitrypsin inhibits ATP-mediated release of interleukin-1β via CD36 and nicotinic acetylcholine receptors. Front Immunol 9:877, doi: 10.3389/fimmu.2018.00877
3. Hiller SD, Heldmann S, Richter K, Jurastow I, Küllmar M, Hecker A, Wilker S, Fuchs-Moll G, Manzini I, Schmalzing G, Kummer W, Padberg W, McIntosh JM, Damm J, Zakrzewicz A, Grau V (2018) β-nicotinamide adenine dinucleotide (β-NAD) inhibits ATP-dependent inflammasome activation in human monocytic cells. Int J Mol Sci 19: 1126, doi: 10.3390/ijms19041126
4. Richter K, Koch C, Perniss A, Wolf PM, Schweda EKH, Wichmann S, Wilker S, Magel I, Sander M, McIntosh JM, Padberg W, Grau V (2018) Phosphocholine-modified lipooligosaccharides of Haemophilus influenzae inhibit ATP-induced IL-1β release by pulmonary epithelial cells. Molecules. 23: E1979, doi: 10.3390/molecules23081979

Text: UGMLC / Veronika Grau

Picture: UGMLC und MHH / Kaiser