Lipopolysaccharide Induces Alveolar Macrophage Necrosis via CD14 and the P2X7 Receptor Leading to Interleukin-1α Release

Immunity. 2015 Apr 21;42(4):640-53. doi: 10.1016/j.immuni.2015.03.007. Epub 2015 Apr 7.

Abstract

Acute lung injury (ALI) remains a serious health issue with little improvement in our understanding of the pathophysiology and therapeutic approaches. We investigated the mechanism that lipopolysaccharide (LPS) induces early neutrophil recruitment to lungs and increases pulmonary vascular permeability during ALI. Intratracheal LPS induced release of pro-interleukin-1α (IL-1α) from necrotic alveolar macrophages (AM), which activated endothelial cells (EC) to induce vascular leakage via loss of vascular endothelial (VE)-cadherin. LPS triggered the AM purinergic receptor P2X7(R) to induce Ca(2+) influx and ATP depletion, which led to necrosis. P2X7R deficiency significantly reduced necrotic death of AM and release of pro-IL-1α into the lung. CD14 was required for LPS binding to P2X7R, as CD14 neutralization significantly diminished LPS induced necrotic death of AM and pro-IL-1α release. These results demonstrate a key role for pro-IL-1α from necrotic alveolar macrophages in LPS-mediated ALI, as a critical initiator of increased vascular permeability and early neutrophil infiltration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury / chemically induced
  • Acute Lung Injury / immunology
  • Acute Lung Injury / pathology
  • Adenosine Triphosphate / metabolism
  • Animals
  • Cadherins / genetics
  • Cadherins / immunology
  • Calcium / metabolism
  • Capillary Permeability / immunology
  • Endothelial Cells / drug effects
  • Endothelial Cells / immunology
  • Endothelial Cells / pathology
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • Interleukin-1alpha / genetics
  • Interleukin-1alpha / immunology*
  • Intubation, Intratracheal
  • Lipopolysaccharide Receptors / genetics
  • Lipopolysaccharide Receptors / immunology*
  • Lipopolysaccharides / pharmacology*
  • Lung / drug effects
  • Lung / immunology
  • Lung / pathology
  • Macrophages, Alveolar / drug effects*
  • Macrophages, Alveolar / immunology
  • Macrophages, Alveolar / pathology
  • Mice
  • Mice, Transgenic
  • Necrosis / chemically induced
  • Necrosis / immunology
  • Necrosis / pathology
  • Neutrophil Infiltration
  • Neutrophils / drug effects
  • Neutrophils / immunology
  • Neutrophils / pathology
  • Protein Precursors / genetics
  • Protein Precursors / immunology
  • Receptors, Purinergic P2X7 / genetics
  • Receptors, Purinergic P2X7 / immunology*
  • Signal Transduction

Substances

  • Cadherins
  • Interleukin-1alpha
  • Lipopolysaccharide Receptors
  • Lipopolysaccharides
  • Protein Precursors
  • Receptors, Purinergic P2X7
  • Adenosine Triphosphate
  • Calcium