The TSC-mTOR pathway regulates macrophage polarization

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Macrophages are able to polarize to proinflammatory M1 or alternative M2 states with distinct phenotypes and physiological functions. How metabolic status regulates macrophage polarization remains not well understood, and here we examine the role of mTOR (mechanistic target of rapamycin), a central metabolic pathway that couples nutrient sensing to regulation of metabolic processes. Using a mouse model in which myeloid lineage-specific deletion of Tsc1 (Tsc1Δ/Δ) leads to constitutive mTOR complex 1 (mTORC1) activation, we find that Tsc1Δ/Δ macrophages are refractory to IL-4-induced M2 polarization, but produce increased inflammatory responses to proinflammatory stimuli. Moreover, mTORC1-mediated downregulation of Akt signalling critically contributes to defective polarization. These findings highlight a key role for the mTOR pathway in regulating macrophage polarization, and suggest how nutrient sensing and metabolic status could be ‘hard-wired’ to control of macrophage function, with broad implications for regulation of type 2 immunity, inflammation and allergy.

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Figure 1: Tsc1Δ/Δ BMDMs have defective M2 polarization and enhanced responses to LPS stimulation.
Figure 2: STAT6 and PPARγ activity are normal in Tsc1Δ/Δ BMDMs.
Figure 3: Constitutive mTORC1 activity attenuates IL-4-induced Akt activation.
Figure 4: Akt signalling is critical for polarization in Tsc1Δ/Δ BMDMs.
Figure 5: M2 polarization in Tsc1Δ/Δ mice is impaired in vivo.
Figure 6: Proposed model for how mTORC1 activity controls macrophage polarization.


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This project was supported by a NIH grant R01AI102964 (to T.H.). A.J.C. is a recipient of a Ford Foundation Predoctoral Fellowship. B.D.M. was supported by a NIH grant R01-CA122617 and I.B.-S. by a LAM Foundation Fellowship. D.M.S. was funded in part by a Julie Martin Mid-Career Award in Aging Research from the American Federation of Aging Research (AFAR) and is an Investigator of the Howard Hughes Medical Institute. D.W.L. is supported by a K99/R00 award from the NIH/NIA (1K99AG041765-01A1). We also thank C.H. Lee for critical reading of the manuscript and S.H. Liu for technical advice.

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V.B. and A.J.C. designed and performed the experiments, analysed the data and wrote the paper. T.H. supervised the project, including experimental design and data analysis, and edited the paper. I.B.-S. and D.W.L. contributed technical expertise. D.M.S. and B.D.M. provided reagents and mice.

Correspondence to Tiffany Horng.

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