The TSC-mTOR pathway regulates macrophage polarization

Vanessa Byles, Anthony J. Covarrubias, Issam Ben-Sahra, Dudley W. Lamming, David M. Sabatini, Brendan D. Manning and Tiffany Horng ()
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Vanessa Byles: Harvard School of Public Health
Anthony J. Covarrubias: Harvard School of Public Health
Issam Ben-Sahra: Harvard School of Public Health
Dudley W. Lamming: Whitehead Institute for Biomedical Research
David M. Sabatini: Whitehead Institute for Biomedical Research
Brendan D. Manning: Harvard School of Public Health
Tiffany Horng: Harvard School of Public Health

Nature Communications, 2013, vol. 4, issue 1, 1-11

Abstract: Abstract 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.

Date: 2013
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DOI: 10.1038/ncomms3834

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