Tsc1 is a Critical Regulator of Macrophage Survival and Function.

BACKGROUND/AIMS Tuberous sclerosis complex 1 (Tsc1) has been shown to regulate M1/M2 polarization of macrophages, but the precise roles of Tsc1 in the function and stability of macrophages are not fully understood. Here we show that Tsc1 is required for regulating the survival, migration and phagocytosis of macrophages. METHODS Mice with Tsc1 homozygous deletion in myeloid cells (LysMCreTsc1(flox/flox); Tsc1 KO) were obtained by crossing Tsc1(flox/flox) mice with mice expressing Cre recombinase under the control of Lysozyme promoter (LysMCre). The apoptosis and growth of macrophages were determined by flow cytometry and Real-time PCR (RT-PCR). The phagocytosis was determined using a Vybrant™ phagocytosis assay kit. The migration of macrophages was determined using transwell migration assay. RESULTS Peritoneal macrophages of Tsc1 KO mice exhibited increased apoptosis and enlarged cell size. Both M1 and M2 phenotypes in Tsc1-deficient macrophages were elevated in steady-state as well as in inflammatory conditions. Tsc1-deficient macrophages demonstrated impaired migration and reduced expression of chemokine receptors including CCR2 and CCR5. Phagocytosis activity and ROS production were enhanced in Tsc1-deficient macrophages. Furthermore, pharmacological inhibition of the mammalian target of rapamycin complex 1 (mTORC1) partially reversed the aberrance of Tsc1-deficient macrophages. CONCLUSION Tsc1 plays a critical role in regulating macrophage survival, function and polarization via inhibition of mTORC1 activity.