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

Cristina Alarcón-Vila,Carlos M Martínez,Pablo Pelegrin,Carlos De Torre-Minguela,Carlos García-Palenciano,Alberto Baroja-Mazo,Juan J Martínez-García,Helios Martínez-Banaclocha

doi:10.7554/elife.60849

Cristina Alarcón-Vila, Carlos M Martínez + Show 6 more

Open Access

https://doi.org/10.7554/elife.60849

Copy DOI

Abstract

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.

Highlights

Purinergic signaling controls many different processes during infection and inflammation (Eltzschig et al, 2012) and the P2X7 receptor is one of the key purinergic receptors in modulating the macrophage functions that orchestrate the inflammatory response (Di Virgilio et al, 2017)
CD14 is a co-receptor of TLR4 important for LPS signaling (Zanoni and Granucci, 2013), so we investigated whether CD14 released after P2X7 receptor activation affect the signaling of LPS in macrophages
Our study shows for first time that the cellular release of CD14 induced by the P2X7 receptor has two functional effects on the innate immune system: (i) it decreases CD14-dependent pro-inflammatory signaling in macrophages and (ii) it decrease bacterial dissemination, improving survival during sepsis

Summary

Introduction

Purinergic signaling controls many different processes during infection and inflammation (Eltzschig et al, 2012) and the P2X7 receptor is one of the key purinergic receptors in modulating the macrophage functions that orchestrate the inflammatory response (Di Virgilio et al, 2017). Immunology and Inflammation eLife digest When the immune system detects an infection, it often launches an inflammatory response to fight off the disease This defense mechanism is activated by a cascade of signaling molecules that can aggravate inflammation, causing it to damage the body’s own tissues and organs. Alarcon-Vila et al found that mice lacking the P2X7 receptor had less CD14 and struggled to eliminate the bacterial infection from their system This increase in bacteria caused excessive damage to the mice’s organs, leading to premature death. These findings suggest that P2X7 plays an important role in preventing the onset of sepsis by helping maintain high levels of CD14 following infection. We found that during sepsis there is a decrease in the extracellular pool of CD14 in P2rx7À/À mice, which results in high bacterial dissemination and a decreased mice survival and reveals that the P2X7 receptor is important for maintaining an optimum level of CD14 and ensuring survival of sepsis

Results

Discussion

Materials and methods