Gm-CSF regulates pulmonary surfactant homeostasis and alveolar macrophage-mediated innate host defense

Annu Rev Physiol. 2002;64:775-802. doi: 10.1146/annurev.physiol.64.090601.113847.

Abstract

Recent studies in transgenic mice have revealed important insights into the roles of GM-CSF in regulation of surfactant homeostasis and lung host defense. Interruption of the GM-CSF signaling pathway by targeted ablation of the GM-CSF gene or its receptor (GM(-/-) or GM Rbetac(-/-) mice, respectively) resulted in pulmonary alveolar proteinosis (PAP) but no hematologic abnormalities. Alveolar macrophages from GM(-/-) mice have reduced capacity for surfactant catabolism, cell adhesion, phagocytosis, bacterial killing, Toll-receptor signaling, and expression of various pathogen-associated molecular pattern recognition receptors, suggesting arrest at an early stage of differentiation. PAP and abnormalities of alveolar macrophage function were corrected by local expression of GM-CSF in the lung, and expression of the transcription factor PU.1 in alveolar macrophages of GM(-/-) mice rescued most defects. Recently, a strong association of auto-antibodies to GM-CSF or GM-CSF receptor gene mutations with PAP has implicated GM-CSF signaling abnormalities in the pathogenesis of PAP in humans. Together, these observations demonstrate that GM-CSF has a critical role in regulation of surfactant homeostasis and alveolar macrophage innate immune functions in the lung.

Publication types

  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism*
  • Homeostasis / physiology
  • Lung / immunology
  • Lung / metabolism
  • Macrophages, Alveolar / immunology*
  • Macrophages, Alveolar / metabolism*
  • Pulmonary Surfactants / metabolism*
  • Signal Transduction / immunology

Substances

  • Pulmonary Surfactants
  • Granulocyte-Macrophage Colony-Stimulating Factor