Sepsis is characterized by a systemic inflammatory response followed by immunosuppression of the host. Metabolic defects and mitochondrial failure are common in immunocompromised patients with sepsis. The NLRP3 inflammasome is important for establishing an inflammatory response after activation by the purinergic P2X7 receptor. Here, we study a cohort of individuals with intra-abdominal origin sepsis and show that patient monocytes have impaired NLRP3 activation by the P2X7 receptor. Furthermore, most sepsis-related deaths are among patients whose NLRP3 activation is profoundly altered. In monocytes from sepsis patients, the P2X7 receptor is associated with mitochondrial dysfunction. Furthermore, activation of the P2X7 receptor results in mitochondrial damage, which in turn inhibits NLRP3 activation by HIF-1α. We show that mortality increases in a mouse model of sepsis when the P2X7 receptor is activated in vivo. These data reveal a molecular mechanism initiated by the P2X7 receptor that contributes to NLRP3 impairment during infection.
P2X7 receptor activation induces the release of different cellular proteins, such as CD14, a glycosylphosphatidylinositol (GPI)-anchored protein to the plasma membrane important for LPS signaling via TLR4. Circulating CD14 has been found at elevated levels in sepsis, but the exact mechanism of CD14 release in sepsis has not been established. Here we show for first time that P2X7 receptor induces the release of CD14 in extracellular vesicles, resulting in a net reduction in macrophage plasma membrane CD14 that functionally affects LPS, but not monophosphoryl lipid A, pro-inflammatory cytokine production. Also, we found that during a murine model of sepsis, P2X7 receptor activity is important for maintaining elevated levels of CD14 in biological fluids and a decrease in its activity results in higher bacterial load and exacerbated organ damage, ultimately leading to premature deaths. Our data reveal that P2X7 is a key receptor for helping to clear sepsis because it maintains elevated concentrations of circulating CD14 during infection.
Hypothesis: There are differences between readings of peripheral blood oxygen saturation when the effect on saturation values of methylene blue is compared with that of isosulfan blue when used in sentinel lymph node biopsy in patients with breast cancer.
Sepsis is a global health priority. Despite thorough studies in mice models, its molecular and cellular basis remain unclear and there is no pharmacological effective treatment other than antimicrobial and supportive therapy. During sepsis, T cells exhaustion compromises patients outcome, and immune checkpoints (ICs) become crucial players in disease management. Here, a total of 425 patients with systemic inflammatory response criteria and 127 controls were studied. Soluble SIGLEC5 (sSIGLEC5) levels in plasma were higher in patients with sepsis compared to the other groups and even higher in those patients with septic-shock. sSIGLEC5 plasma levels were higher in non-survivors than in survivors and ROC curves analysis revealed sSIGLEC5 as a survival marker (cut-off ≤ 523.6 ng/mL). In vitro experiments illustrated how SIGLEC5 impaired CD8+ proliferation through binding to PSGL1. Blocking the SIGLEC5/PSGL1 axis reverted the latter effect. Mechanistically, SIGLEC5 overexpression was driven by HIF1α. Exogenous sSIGLEC5 accelerated death and magnified acute lung injury in mice models. Our data demonstrates how plasma sSIGLEC5 level on admission predicts death and stratifies patients with sepsis. This molecule exhibits the hallmarks of an IC ligand.
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