CD14 release induced by P2X7 receptor restricts inflammation and increases survival during sepsis

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.


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Referring to the sample size used in figures 1 and 2, we designed and performed the experiments based in our previous publications (de Torre-Minguela et al., 2016;Barberá-Cremades et al., 2016). This information can be found in figure legends, where each dot represents the result obtained by the use of a single bone marrow-derived macrophage culture obtained from one single mouse. Concerning figures 3, 4, 5 and 6, the animals/human patients sample size was determined based in scientific literature (Csóka et al., 2015;Santana et al., 2015;Martínez-García et al., 2019). This information can be found in figure legends, where each dot represents one independent mouse/human patient. The sample size was determined taking into account that we want to obtain a statistical power of 95% and a significant difference between the results of 0.05% using a restrictive nonparametric test. II.
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