Macrophages are key orchestrators of the innate immune response with a dynamic role in the promotion and resolution of inflammation. Macrophage polarization to a pro-inflammatory or anti-inflammatory phenotype must be tightly controlled to maintain appropriate responses to stimuli as well as to maintain tissue homeostasis. The
nutrient and energy sensor Mammalian Target of Rapamycin (mTOR) integrates upstream signals from the PI3K/Akt pathway to orchestrate cellular protein, lipid, and glucose metabolism. This key metabolic pathway has been implicated in T-helper cell skewing and in the innate immune regulation. The mechanisms of innate immune
regulation by mTOR are currently unclear as most studies use pharmacological inhibitors with potential off target effects. In this study, we use a novel model of TSC1 deficiency in myeloid lineage cells to elucidate a role for mTOR in macrophage polarization. We show, for the first time, that Tsc1-deficiency and constitutive mTORC1
activity in macrophages leads to a marked defect in M2 polarization when stimulated with the Th2 cytokine IL-4. Tsc1-deficient macrophages display attenuated Akt signaling in response to IL-4 consistent with negative feedback of mTORC1 on upstream
IRS2/PI3K signaling, and we demonstrate that this parallel signaling pathway is critical for induction of a subset of M2 markers. Tsc1-deficient macrophages fail to upregulate the M2 genes Pgc-1!, Arg-1, Fizz-1, and Mgl1 in addition to other M2 markers despite
normal STAT6 signaling in response to IL-4. Consistent with downregulation of Pgc-1!, Tsc1-deficient macrophages also display defects in fatty acid metabolism and mitchochondrial biogenesis. Furthermore, LPS stimulation in Tsc-1 deficient macrophages leads to an enhanced inflammatory response with increased production of
pro-inflammatory cytokines. We believe that Tsc1-deficient macrophages are a model of constitutive mTORC1 activity akin to obesity, where chronic nutrient excess leads to increases in mTORC1 activity, attenuation of IRS/PI3K/Akt signaling, and defective M2
polarization of macrophages in metabolic tissues.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/17122 |
| Date | January 2013 |
| Creators | Byles, Vanessa A. |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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