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.
Highlights
Interleukin-1β (IL-1β) is a pro-inflammatory cytokine of innate immunity that plays a seminal role in host defense [1]
Thereafter, 100 μM BzATP, a P2X7 receptor (P2X7R) agonist [40], was applied for 30 min in presence and absence of endogenous CRP (eCRP) and IL-1β concentrations were measured in cell culture supernatants
The activity of eCRP depends on the Ca2+-dependent interaction with a small molecule, presumably PC [14, 15], and on nicotinic acetylcholine (ACh) receptors (nAChRs) subunits α7, α9, and α10
Summary
Interleukin-1β (IL-1β) is a pro-inflammatory cytokine of innate immunity that plays a seminal role in host defense [1]. Secretion of monocytic IL-1β into the circulation in response to severe multiple trauma, may be more harmful than beneficial, as IL-1β is swept away from the site of inflammation, and high blood plasma levels can cause systemic inflammatory response syndrome (SIRS) and multi organ dysfunction syndrome (MODS) [2,3,4,5]. Ligands of toll-like receptors are typical first signals inducing pro-IL-1β synthesis, and extracellular ATP is a typical second signal that activates the ATP-sensitive P2X7 receptor (P2X7R), induces NLRP3 (NACHT, LRR, and PYD domainscontaining protein 3) inflammasome assembly, caspase-1 activation, pro-IL-1β cleavage, and secretion of mature IL-1β [7,8,9,10,11]. The secretion of IL-18 and high mobility group box 1 protein (HMGB1) depends on inflammasome activation [7,8,9,10,11,12,13]. Apart from the ATP-induced pathway typical for trauma-associated sterile inflammation, several alternative mechanisms of IL-1β maturation are activated during infection [1]
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