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Sphingolipid-mediated inhibition of apoptotic cell clearance by alveolar macrophages

Daniela N Petrusca1, Yuan Gu, Jeremy J Adamowicz

  • 1Department of Medicine, Indiana University, Indianapolis, Indiana 46202, USA.

The Journal of Biological Chemistry
|October 20, 2010
PubMed

Insights

High ceramide levels in the lungs impair the ability of alveolar macrophages to clear apoptotic cells, a process crucial for preventing emphysema inflammation. This ceramide-induced defect is linked to cigarette smoke exposure and involves sphingosine production.

Area of Science:

  • Pulmonary Medicine
  • Cell Biology
  • Biochemistry

Background:

  • Decreased clearance of apoptotic cells (efferocytosis) by alveolar macrophages (AM) is implicated in emphysema pathogenesis.
  • Cigarette smoking (CS) increases lung ceramides, potentially contributing to AM dysfunction and cell death accumulation.

Purpose of the Study:

  • To investigate the hypothesis that ceramides inhibit AM efferocytosis.
  • To elucidate the mechanism by which ceramides impair efferocytosis and its relevance to CS-induced lung injury.

Main Methods:

  • Primary rat and human AM were treated with endogenous or exogenous ceramides to assess phagocytosis of apoptotic Jurkat cells.
  • In vivo studies involved intratracheal ceramide instillation in rats to evaluate efferocytosis of apoptotic thymocytes.
  • Mechanistic studies examined the role of sphingosine and Rac1 signaling in ceramide-mediated efferocytosis impairment.

Main Results:

  • Ceramide treatment, regardless of molecular species, dose-dependently impaired AM efferocytosis.
  • In vivo ceramide elevation significantly reduced apoptotic cell clearance by resident AM.
  • Ceramide-induced efferocytosis inhibition was dependent on sphingosine generation and impaired Rac1 recruitment, which could be rescued by Rac1 activation.
  • CS exposure increased AM ceramides, inhibited Rac1 recruitment, and profoundly impaired AM efferocytosis via sphingosine production.

Conclusions:

  • Excessive lung ceramides, exacerbated by CS, impair AM efferocytosis through sphingosine generation and disruption of Rac1 signaling.
  • This impaired efferocytosis may amplify lung injury in emphysema by promoting cell apoptosis and hindering clearance.
  • Targeting ceramide metabolism could be a therapeutic strategy for emphysema.

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