C1P Attenuates Lipopolysaccharide-Induced Acute Lung Injury by Preventing NF-κB Activation in Neutrophils

Abstract

Recently, ceramide-1-phosphate (C1P) has been shown to modulate acute inflammatory events. Acute lung injury (Arnalich et al. 2000. Infect. Immun. 68: 1942–1945) is characterized by rapid alveolar injury, lung inflammation, induced cytokine production, neutrophil accumulation, and vascular leakage leading to lung edema. The aim of this study was to investigate the role of C1P during LPS-induced acute lung injury in mice. To evaluate the effect of C1P, we used a prophylactic and therapeutic LPS-induced ALI model in C57BL/6 male mice. Our studies revealed that intrapulmonary application of C1P before (prophylactic) or 24 h after (therapeutic) LPS instillation decreased neutrophil trafficking to the lung, proinflammatory cytokine levels in bronchoalveolar lavage, and alveolar capillary leakage. Mechanistically, C1P inhibited the LPS-triggered NF-κB levels in lung tissue in vivo. In addition, ex vivo experiments revealed that C1P also attenuates LPS-induced NF-κB phosphorylation and IL-8 production in human neutrophils. These results indicate C1P playing a role in dampening LPS-induced acute lung inflammation and suggest that C1P could be a valuable candidate for treatment of ALI.

Bilirubin suppresses Th17 immunity in colitis by upregulating CD39

“…Modulation of Th17 cells involves P2 signaling and inhibition of P2X7 activation decreases IL-6 levels and STAT-3 effects, both impacting Th17 cell differentiation (44). These mechanisms may act in concert with induction of CD39, which shifts the balance towards P1 adenosinemediated signaling and modulates Th17 cell pathogenic potential (18).…”

Sphingolipids role in the regulation of inflammatory response: From leukocyte biology to bacterial infection

“…CerK knockout mice display severe neutropenia, which seems to be due to entrapment of neutrophils in bone marrow . Conversely, C1P administration decreases the pro‐inflammatory state of neutrophils in patients with chronic obstructive lung disease . In human peripheral blood mononuclear cells, C1P suppresses LPS‐mediated production of pro‐inflammatory cytokines, including TNF, interleukin (IL) IL‐6, IL‐8, and IL‐1β, and inhibits TNF‐α converting enzyme, which triggers TNF‐α production …”

Sphingolipids in neutrophil function and inflammatory responses: Mechanisms and implications for intestinal immunity and inflammation in ulcerative colitis

“…Mice also presented decreased levels of pro-inflammatory cytokines IL-1β, IL-6, MIP-1 and the neutrophil chemoattractant CXCL1. Mechanistically, the authors demonstrated that human neutrophils from COPD patients have increased levels of NFkB-driven IL-8 production and the phenotype is reversed with C1P treatment (Baudiss et al, 2015; Baudiss et al, 2016). …”