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      The TSC-mTOR pathway regulates macrophage polarization

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          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 ( Tsc1 Δ/Δ) leads to constitutive mTOR Complex 1 (mTORC1) activation, we find that Tsc1 Δ/Δ macrophages are refractory to IL-4 induced M2 polarization, but produce increased inflammatory responses to proinflammatory stimuli. Moreover, mTORC1-mediated downregulation of Akt signaling 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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          Most cited references36

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          Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B.

          Glycogen synthase kinase-3 (GSK3) is implicated in the regulation of several physiological processes, including the control of glycogen and protein synthesis by insulin, modulation of the transcription factors AP-1 and CREB, the specification of cell fate in Drosophila and dorsoventral patterning in Xenopus embryos. GSK3 is inhibited by serine phosphorylation in response to insulin or growth factors and in vitro by either MAP kinase-activated protein (MAPKAP) kinase-1 (also known as p90rsk) or p70 ribosomal S6 kinase (p70S6k). Here we show, however, that agents which prevent the activation of both MAPKAP kinase-1 and p70S6k by insulin in vivo do not block the phosphorylation and inhibition of GSK3. Another insulin-stimulated protein kinase inactivates GSK3 under these conditions, and we demonstrate that it is the product of the proto-oncogene protein kinase B (PKB, also known as Akt/RAC). Like the inhibition of GSK3 (refs 10, 14), the activation of PKB is prevented by inhibitors of phosphatidylinositol (PI) 3-kinase.
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            Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance.

            Obesity and insulin resistance, the cardinal features of metabolic syndrome, are closely associated with a state of low-grade inflammation. In adipose tissue chronic overnutrition leads to macrophage infiltration, resulting in local inflammation that potentiates insulin resistance. For instance, transgenic expression of Mcp1 (also known as chemokine ligand 2, Ccl2) in adipose tissue increases macrophage infiltration, inflammation and insulin resistance. Conversely, disruption of Mcp1 or its receptor Ccr2 impairs migration of macrophages into adipose tissue, thereby lowering adipose tissue inflammation and improving insulin sensitivity. These findings together suggest a correlation between macrophage content in adipose tissue and insulin resistance. However, resident macrophages in tissues display tremendous heterogeneity in their activities and functions, primarily reflecting their local metabolic and immune microenvironment. While Mcp1 directs recruitment of pro-inflammatory classically activated macrophages to sites of tissue damage, resident macrophages, such as those present in the adipose tissue of lean mice, display the alternatively activated phenotype. Despite their higher capacity to repair tissue, the precise role of alternatively activated macrophages in obesity-induced insulin resistance remains unknown. Using mice with macrophage-specific deletion of the peroxisome proliferator activated receptor-gamma (PPARgamma), we show here that PPARgamma is required for maturation of alternatively activated macrophages. Disruption of PPARgamma in myeloid cells impairs alternative macrophage activation, and predisposes these animals to development of diet-induced obesity, insulin resistance, and glucose intolerance. Furthermore, gene expression profiling revealed that downregulation of oxidative phosphorylation gene expression in skeletal muscle and liver leads to decreased insulin sensitivity in these tissues. Together, our findings suggest that resident alternatively activated macrophages have a beneficial role in regulating nutrient homeostasis and suggest that macrophage polarization towards the alternative state might be a useful strategy for treating type 2 diabetes.
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              Conditional gene targeting in macrophages and granulocytes using LysMcre mice.

              Conditional mutagenesis in mice has recently been made possible through the combination of gene targeting techniques and site-directed mutagenesis, using the bacteriophage P1-derived Cre/loxP recombination system. The versatility of this approach depends on the availability of mouse mutants in which the recombinase Cre is expressed in the appropriate cell lineages or tissues. Here we report the generation of mice that express Cre in myeloid cells due to targeted insertion of the cre cDNA into their endogenous M lysozyme locus. In double mutant mice harboring both the LysMcre allele and one of two different loxP-flanked target genes tested, a deletion efficiency of 83-98% was determined in mature macrophages and near 100% in granulocytes. Partial deletion (16%) could be detected in CD11c+ splenic dendritic cells which are closely related to the monocyte/macrophage lineage. In contrast, no significant deletion was observed in tail DNA or purified T and B cells. Taken together, LysMcre mice allow for both specific and highly efficient Cre-mediated deletion of loxP-flanked target genes in myeloid cells.
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                Author and article information

                Journal
                101528555
                37539
                Nat Commun
                Nat Commun
                Nature communications
                2041-1723
                16 December 2013
                2013
                31 December 2013
                : 4
                : 10.1038/ncomms3834
                Affiliations
                [1 ]Department of Genetics & Complex Diseases, Harvard School of Public Health, Boston, Massachusetts
                [2 ]Whitehead Institute for Biomedical Research, Cambridge, MA 02142; Department of Biology, MIT, Cambridge, MA 02139; Howard Hughes Medical Institute, MIT, Cambridge, MA 02139; Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, MA 02142; The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139
                Author notes
                Corresponding author: Tiffany Horng, Harvard School of Public Health, 655 Huntington Ave, II-115, Boston, MA 02115, Ph: (617) 432-7526, F: (617) 432-5236, thorng@ 123456hsph.harvard.edu
                [3]

                These authors contributed equally to this work

                Article
                NIHMS536072
                10.1038/ncomms3834
                3876736
                24280772
                6e761055-67b7-46ad-9821-7034f9ae621e

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                History
                Funding
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R37 AI047389 || AI
                Funded by: National Cancer Institute : NCI
                Award ID: R01 CA129105 || CA
                Funded by: National Cancer Institute : NCI
                Award ID: R01 CA103866 || CA
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI102964 || AI
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI047389 || AI
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