Journal article

Publication year: 2018

Journal: Frontiers in Immunology

Volume number: 9

ISSN: 1664-3224

Open access status: Gold

DOI Link: https://doi.org/10.3389/fimmu.2018.01604

Publisher: Frontiers Media

Abstract: 
Blood levels of the acute phase reactant C-reactive protein (CRP) are frequently measured as a clinical marker for inflammation, but the biological functions of CRP are still controversial. CRP is a phosphocholine (PC)-binding pentraxin, mainly produced in the liver in response to elevated levels of interleukin-1 beta (IL-1 beta) and of the IL-1 beta-dependent cytokine IL6. While both cytokines play important roles in host defense, excessive systemic IL-1 beta levels can cause life-threatening diseases such as trauma-associated systemic inflammation. We hypothesized that CRP acts as a negative feedback regulator of monocytic IL-1 beta maturation and secretion. Here, we demonstrate that CRP, in association with PC, efficiently reduces ATP-induced inflammasome activation and IL-1 beta release from human peripheral blood mononuclear leukocytes and monocytic U937 cells. Effective concentrations are in the range of marginally pathologic CRP levels (IC50 = 4.9 mu g/ml). CRP elicits metabotropic functions at nicotinic acetylcholine (ACh) receptors (nAChRs) containing subunits alpha 7, alpha 9, and alpha 10 and suppresses the function of ATP-sensitive P2X7 receptors in monocytic cells. Of note, CRP does not induce ion currents at conventional nAChRs, suggesting that CRP is a potent nicotinic agonist controlling innate immunity without entailing the risk of adverse effects in the nervous system. In a prospective study on multiple trauma patients, IL-1 beta plasma concentrations negatively correlated with preceding CRP levels, whereas inflammasome-independent cytokines IL-6, IL-18, and INF-alpha positively correlated. In conclusion, PC laden CRP is an unconventional nicotinic agonist that potently inhibits ATP-induced inflammasome activation and might protect against trauma-associated sterile inflammation.

Harvard Citation style: Richter, K., Sagawe, S., Hecker, A., Küllmar, M., Askevold, I., Damm, J., et al. (2018) C-Reactive Protein Stimulates Nicotinic Acetylcholine Receptors to Control ATP-Mediated Monocytic Inflammasome Activation, Frontiers in Immunology, 9, Article 1604. https://doi.org/10.3389/fimmu.2018.01604

APA Citation style: Richter, K., Sagawe, S., Hecker, A., Küllmar, M., Askevold, I., Damm, J., Heldmann, S., Pöhlmann, M., Ruhrmann, S., Sander, M., Schlüter, K., Wilker, S., König, I., Kummer, W., Padberg, W., Hone, A., McIntosh, J., Zakrzewicz, A., Koch, C., ...Grau, V. (2018). C-Reactive Protein Stimulates Nicotinic Acetylcholine Receptors to Control ATP-Mediated Monocytic Inflammasome Activation. Frontiers in Immunology. 9, Article 1604. https://doi.org/10.3389/fimmu.2018.01604