Out of breath: GM-CSFRalpha mutations disrupt surfactant homeostasis

Abstract

Pulmonary alveolar proteinosis (PAP) is a rare disorder in which surfactant homeostasis in the lung is impaired, causing respiratory distress and, in severe cases, respiratory failure. Most cases of PAP are associated with the formation of autoantibodies against the cytokine granulocyte/macrophage colony-stimulating factor (GM-CSF), which is required for normal surfactant homeostasis and lung function. New studies now identify three patients in whom PAP was caused by mutations in the gene encoding the ligand-binding alpha chain of the GM-CSF receptor.

Figure 1.

Mutations of GM-CSFRα disrupt alveolar macrophage functions and surfactant homeostasis. (top) (A) GM-CSF binds to GM-CSF receptor α (GM-CSFRα) to form a low-affinity complex, which then interacts with the β complex (two β chains constitutively bound to JAK2) to form the high-affinity hexameric receptor complex (B). Lateral movement and aggregation of two such complexes form the active dodecamer signaling receptor (not depicted), allowing cross-phosphorylation of the JAK2 molecules and the β subunit. Activated JAK2 phosphorylates the transcription factors STAT5, which then dimerizes and migrates to the nucleus where it induces the expression of the PU.1 transcription factor gene (C). This results in the expression of various PU.1-dependent genes and subsequent activation of multiple phagocytic functions, such as adhesion, phagocytosis, killing, signaling through TLR4, and the release of IL-12 and -18, which in turn induce release of IFN-γ by T and NK cells. This pathway also induces surfactant catabolism (D), although the mechanistic details of this pathway remain to be defined. (bottom) GM-CSF signaling is abrogated in phagocytes from patients with primary PAP who fail to express functional GM-CSFRα molecules (E). In these conditions, surfactant is still taken up by the alveolar macrophages, but is not properly catabolized, leading to progressive surfactant accumulation within the phagocyte (producing the typical foamy appearing alveolar macrophages) and in the alveolar space.