Survival and Homeostasis of Alveolar Macrophages in Vivo Depend on mTOR Signaling

Alveolar homeostasis depends on tissue-resident professional phagocytes known as alveolar macrophages (AMs) that catabolize pulmonary surfactant. Pulmonary alveolar proteinosis (PAP) arises from impaired surfactant clearance due to loss or dysfunction of AMs, most commonly from disrupted GM-CSF-dependent AM homeostasis and less frequently from congenital defects in surfactant synthesis or processing. PAP has also been reported as a pulmonary toxicity associated with mTOR inhibitor-based immunosuppressive therapy. Although mTOR activity regulates macrophage metabolism and proliferation, its requirement for AM survival and lipid homeostasis remains unclear. Here, we examined the role of mTOR in AM survival and surfactant homeostasis, using complementary genetic and pharmacologic approaches in vivo, and GM-CSF-driven AM-like cell culture models in vitro. Myeloid-specific deletion of mTOR caused progressive, preferential depletion of AMs among tissue-resident macrophage populations, accompanied by impaired phagocytosis, intracellular lipid accumulation, and development of PAP-like lung pathology. In vivo, pharmacologic mTOR inhibition with temsirolimus reproduced key features of genetic mTOR deletion, including AM depletion, apoptosis, lipid accumulation, and PAP-like pathology. In vitro, mTOR activity was required to sustain GM-CSF-dependent expansion, maturation, and survival of AM-like cells. Mechanistically, mTOR loss reduced expression of PPARγ and pro-survival Bcl-2 family members, linking mTOR activity to AM viability and lipid handling capacity. In summary, these findings identify mTOR as a nonredundant, cell-intrinsic regulator of alveolar macrophage survival and function required to maintain alveolar homeostasis. This work provides experimental support for AM-intrinsic mechanisms contributing to mTOR inhibitor-associated pulmonary toxicity, including PAP.