Macrophages acquire distinct phenotypes during tissue stress and inflammatory responses, but the mechanisms that regulate the macrophagepolarization are poorly defined. Here we show that tuberous sclerosis complex 1 (TSC1) is a critical regulator of M1 and M2 phenotypes of macrophages. Mice with myeloid-specific deletion of TSC1 exhibit enhanced M1 response and spontaneously develop M1-related inflammatorydisorders. However, TSC1-deficient mice are highly resistant to M2-polarized allergic asthma. Inhibition of the mammalian target of rapamycin (mTOR) fails to reverse the hypersensitive M1 response of TSC1-deficient macrophages, but efficiently rescues the defective M2 polarization. Deletion of mTOR also fails to reverse the enhanced inflammatory response of TSC1-deficient macrophages. Molecular studies indicate that TSC1inhibits M1 polarization by suppressing the Ras GTPase-Raf1-MEK-ERK pathway in mTOR-independent manner, whereas TSC1 promotes M2 properties by mTOR-dependent CCAAT/enhancer-binding protein-β pathways. Overall, these findings define a key role for TSC1 in orchestratingmacrophagepolarization via mTOR-dependent and independent pathways.

Zhu LN, Yang T, Li LJ, Sun LN, Hou YZ, Hu XL, Zhang LJ, Tian HL, Zhao QJ, Peng JX, Zhang HB, Wang RY, Yang ZZ, Zhang LF, Zhao Y*. (2014) TSC1 controls macrophage polarization to prevent inflammatory disease. Nature Communications, 5:4696.