10.3389/fimmu.2018.01604.s001 Katrin Richter Katrin Richter Sabrina Sagawe Sabrina Sagawe Andreas Hecker Andreas Hecker Mira Küllmar Mira Küllmar Ingolf Askevold Ingolf Askevold Jelena Damm Jelena Damm Sarah Heldmann Sarah Heldmann Michael Pöhlmann Michael Pöhlmann Sophie Ruhrmann Sophie Ruhrmann Michael Sander Michael Sander Klaus-Dieter Schlüter Klaus-Dieter Schlüter Sigrid Wilker Sigrid Wilker Inke R. König Inke R. König Wolfgang Kummer Wolfgang Kummer Winfried Padberg Winfried Padberg Arik J. Hone Arik J. Hone J. Michael McIntosh J. Michael McIntosh Anna Teresa Zakrzewicz Anna Teresa Zakrzewicz Christian Koch Christian Koch Veronika Grau Veronika Grau Presentation_1_C-Reactive Protein Stimulates Nicotinic Acetylcholine Receptors to Control ATP-Mediated Monocytic Inflammasome Activation.pdf Frontiers 2018 C-reactive protein interleukin-1β NLRP3 inflammasome monocytes nicotinic acetylcholine receptors sterile inflammation 2018-07-30 04:13:05 Presentation https://frontiersin.figshare.com/articles/presentation/Presentation_1_C-Reactive_Protein_Stimulates_Nicotinic_Acetylcholine_Receptors_to_Control_ATP-Mediated_Monocytic_Inflammasome_Activation_pdf/6875774 <p>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-1β (IL-1β) and of the IL-1β-dependent cytokine IL-6. While both cytokines play important roles in host defense, excessive systemic IL-1β 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-1β maturation and secretion. Here, we demonstrate that CRP, in association with PC, efficiently reduces ATP-induced inflammasome activation and IL-1β release from human peripheral blood mononuclear leukocytes and monocytic U937 cells. Effective concentrations are in the range of marginally pathologic CRP levels (IC<sub>50</sub> = 4.9 µg/ml). CRP elicits metabotropic functions at nicotinic acetylcholine (ACh) receptors (nAChRs) containing subunits α7, α9, and α10 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-1β plasma concentrations negatively correlated with preceding CRP levels, whereas inflammasome-independent cytokines IL-6, IL-18, and TNF-α 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.</p>