Precision control of mTORC1 is crucial for the maintenance and IL-13 responsiveness of alveolar macrophages

•The TSC1-mTOR pathway is essential for the homeostasis of AMs.•TSC1 has to precisely control mTOR to maintain a delicate balance between AMs proliferation and cell death.•The TSC1-mTOR pathway mediates IL-13-promoted AM homeostasis. Alveolar macrophages (AMs) are the lung resident macrophages critically involved in pulmonary homeostasis and immune response. Recent researches have uncovered a diversity of regulators responsible for the development, maintenance, and function of AMs. Nevertheless, the molecular underpinnings that determine the developmental and functional specification of AMs remain incompletely understood. Here, we investigated the role of the TSC1-mTOR pathway in murine AMs by genetic ablating Tsc1 or mTor alleles through Cd11c-Cre or LysM-Cre. Flow cytometry analyses revealed a prominent decrease in AMs in Tsc1f/f-Cd11c-Cre and Tsc1f/f/-LysM-Cre mice. Moreover, a reduction in AMs was also noted in mTorf/f-Cd11c-Cre or Rptorf/f-Cd11c-Cre mice. Further evidence implicated that elevation in cell death, most likely aberrant apoptosis or/and necroptosis, might be attributable to disrupted AM homeostasis. Whereas a diversity of cytokines involved in AM homeostasis and function triggered mTOR activation, only the IL-13 signaling, particularly Jak1 and Stat3 activation, was affected by TSC1 in macrophages. Further, select genes induced by IL-13, including AM surface markers such as Pparg, Fabp4/5, Nfil3 and Car4, and M2 hallmarks such as Arg1, Fizz, Ym1 and Clec7a were fine-tuned by the TSC1-mTOR pathway. Therefore, our results demonstrated that the TSC1-mTOR pathway has a crucial role in the homeostasis and functional specification of AMs through integrating cytokine signaling with metabolic cues.