Richter, KatrinKatrinRichterSagawe, SabrinaSabrinaSagaweHecker, AndreasAndreasHeckerKüllmar, MiraMiraKüllmarAskevold, IngolfIngolfAskevoldDamm, JelenaJelenaDammHeldmann, SarahSarahHeldmannPöhlmann, MichaelMichaelPöhlmannRuhrmann, SophieSophieRuhrmannSander, MichaelMichaelSanderSchlüter, Klaus-DieterKlaus-DieterSchlüterWilker, SigridSigridWilkerKönig, Inke R.Inke R.KönigKummer, WolfgangWolfgangKummerPadberg, WinfriedWinfriedPadbergHone, Arik J.Arik J.HoneMcIntosh, J. MichaelJ. MichaelMcIntoshZakrzewicz, Anna TeresaAnna TeresaZakrzewiczKoch, ChristianChristianKochGrau, VeronikaVeronikaGrau2022-11-182019-05-202022-11-182018http://nbn-resolving.de/urn:nbn:de:hebis:26-opus-146319https://jlupub.ub.uni-giessen.de/handle/jlupub/9466http://dx.doi.org/10.22029/jlupub-8854Blood 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-1beta (IL-1beta) and of the IL-1beta-dependent cytokine IL-6. While both cytokines play important roles in host defense, excessive systemic IL-1beta levels can cause life-threatening diseases such as trauma-associated systemic inflammation. We hypothesized that CRP acts as a negative feed back regulator of monocytic IL-1beta maturation and secretion. Here, we demonstrate that CRP, in association with phosphocholine, efficiently reduces ATP-mediated 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 (IC50 = 4.9 µg/ml). CRP elicits metabotropic functions at nicotinic acetylcholine receptors (nAChR) containing subunits alpha7, alpha9 and alpha10 and suppresses the function of ATP-sensitive P2X7 receptors in monocytic cells. Of note, CRP does not induce ion currents at conventional nAChR, 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-1beta plasma concentrations negatively correlated with preceding CRP levels, whereas inflammasome-independent cytokines IL 6 and TNF-alpha positively correlated. In conclusion, phosphocholine-laden CRP is an unconventional nicotinic agonist that potently inhibits ATP-induced inflammasome activation and has the potential to protect against trauma-associated sterile inflammation.enNamensnennung 4.0 InternationalC-reactive proteininterleukin-1βNLRP3 inflammasomemonocytesnicotinic acetylcholine receptorsddc:610