C-Reactive Protein Stimulates Nicotinic Acetylcholine Receptors to Control ATP-Mediated Monocytic Inflammasome Activation

Front Immunol. 2018 Jul 30;9:1604. doi: 10.3389/fimmu.2018.01604. eCollection 2018.

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-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 (IC50 = 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.

Keywords: C-reactive protein; NLRP3 inflammasome; interleukin-1β; monocytes; nicotinic acetylcholine receptors; sterile inflammation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Biomarkers
  • C-Reactive Protein / immunology*
  • C-Reactive Protein / pharmacology
  • Cells, Cultured
  • Cytokines / immunology
  • Cytokines / metabolism
  • Humans
  • Inflammasomes / immunology*
  • Inflammasomes / metabolism
  • Inflammation* / immunology
  • Inflammation* / metabolism
  • Interleukin-1beta / immunology
  • Interleukin-1beta / metabolism
  • Male
  • Middle Aged
  • Receptors, Nicotinic / immunology
  • Receptors, Nicotinic / metabolism
  • Receptors, Purinergic P2X7 / immunology
  • Receptors, Purinergic P2X7 / metabolism

Substances

  • Biomarkers
  • Cytokines
  • Inflammasomes
  • Interleukin-1beta
  • Receptors, Nicotinic
  • Receptors, Purinergic P2X7
  • C-Reactive Protein

Associated data

  • DRKS/DRKS00010991