Protective and pathogenic roles for TRAIL signaling. (A) During infection with S. pneumoniae, neutrophils that migrate to the lungs produce soluble TRAIL, which then promotes apoptosis of infected alveolar macrophages. Macrophage apoptosis limits bacterial spread and restricts the magnitude and duration of pathology-inducing inflammation. (B) TRAIL (soluble or membrane-bound) produced by structural cells in small arteries induces the proliferation of smooth muscle cells, possibly via TRAIL-R3, and may also promote the survival of other cells in the arterioles, resulting in increased vascular remodeling and PAH.