Key Points
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Mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that is present in two complexes: mTORC1 and mTORC2. mTORC1 is the main energy and nutrient sensor of the cell: it senses the presence of amino acids, glucose, lipids and ATP to enable efficient activation of the network in response to growth factors, Toll-like receptor (TLR) ligands and cytokines.
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Activation of the mTOR pathway usually promotes an anabolic response that induces the synthesis of nucleic acids, proteins and lipids. In addition, it stimulates glycolysis and mitochondrial respiration. Emerging data suggest that this metabolic reconfiguration is required for specific effector functions in myeloid cells.
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Translational control of gene expression in myeloid immune cells has emerged as one way in which mTORC1 controls cellular processes such as migration, expression of type I interferon and pro-inflammatory or anti-inflammatory cytokines, and metabolic reprogramming.
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Counterintuitively, inhibition of mTORC1 during TLR triggering generally promotes interleukin-12 (IL-12) production and inhibits expression of IL-10 and type I interferon by dendritic cells (DCs); it also augments their T cell-stimulatory capacity. Inhibition of mTORC2 enhances a pro-inflammatory response and IL-12 production in DCs.
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Inhibition of mTORC1 in macrophages promotes autophagy, which is important for intracellular pathogen killing and clearance of ingested complex lipids such as low-density lipoprotein (LDL) cholesterol.
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mTORC2 is especially important for cell polarity and chemotaxis in neutrophils and mast cells. mTORC2 controls the leading edge as well as tail retraction during chemotactic migration.
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Activation of mTORC1 in NK cells by IL-15 triggers a glycolytic response, which is important for their proliferation and acquisition of cytotoxicity.
Abstract
The innate immune system is central for the maintenance of tissue homeostasis and quickly responds to local or systemic perturbations by pathogenic or sterile insults. This rapid response must be metabolically supported to allow cell migration and proliferation and to enable efficient production of cytokines and lipid mediators. This Review focuses on the role of mammalian target of rapamycin (mTOR) in controlling and shaping the effector responses of innate immune cells. mTOR reconfigures cellular metabolism and regulates translation, cytokine responses, antigen presentation, macrophage polarization and cell migration. The mTOR network emerges as an integrative rheostat that couples cellular activation to the environmental and intracellular nutritional status to dictate and optimize the inflammatory response. A detailed understanding of how mTOR metabolically coordinates effector responses by myeloid cells will provide important insights into immunity in health and disease.
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References
Laplante, M. & Sabatini, D. M. mTOR signaling in growth control and disease. Cell 149, 274–293 (2012).
Shimobayashi, M. & Hall, M. N. Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat. Rev. Mol. Cell Biol. 15, 155–162 (2014).
Haidinger, M. et al. A versatile role of mammalian target of rapamycin in human dendritic cell function and differentiation. J. Immunol. 185, 3919–3931 (2010).
Sathaliyawala, T. et al. Mammalian target of rapamycin controls dendritic cell development downstream of Flt3 ligand signaling. Immunity 33, 597–606 (2010).
Lehman, J. A., Calvo, V. & Gomez-Cambronero, J. Mechanism of ribosomal p70S6 kinase activation by granulocyte macrophage colony-stimulating factor in neutrophils: cooperation of a MEK-related, THR421/SER424 kinase and a rapamycin-sensitive, m-TOR-related THR389 kinase. J. Biol. Chem. 278, 28130–28138 (2003).
Fukao, T. et al. PI3K-mediated negative feedback regulation of IL-12 production in DCs. Nat. Immunol. 3, 875–881 (2002).
Ohtani, M. et al. Mammalian target of rapamycin and glycogen synthase kinase 3 differentially regulate lipopolysaccharide-induced interleukin-12 production in dendritic cells. Blood 112, 635–643 (2008).
Weichhart, T. et al. The TSC–mTOR signaling pathway regulates the innate inflammatory response. Immunity 29, 565–577 (2008). References 7 and 8 were the first to describe immunostimulatory effects of rapamycin in DCs that lead to enhanced T cell activation.
Weichhart, T. et al. Inhibition of mTOR blocks the anti-inflammatory effects of glucocorticoids in myeloid immune cells. Blood 117, 4273–4283 (2011).
Schmitz, F. et al. Mammalian target of rapamycin (mTOR) orchestrates the defense program of innate immune cells. Eur. J. Immunol. 38, 2981–2992 (2008).
Turnquist, H. R. et al. mTOR and GSK-3 shape the CD4+ T-cell stimulatory and differentiation capacity of myeloid DCs after exposure to LPS. Blood 115, 4758–4769 (2010).
Jiang, Q. et al. mTOR kinase inhibitor AZD8055 enhances the immunotherapeutic activity of an agonist CD40 antibody in cancer treatment. Cancer Res. 71, 4074–4084 (2011).
Lorne, E. et al. Participation of mammalian target of rapamycin complex 1 in Toll-like receptor 2- and 4-induced neutrophil activation and acute lung injury. Am. J. Respir. Cell. Mol. Biol. 41, 237–245 (2009).
Zhu, L. et al. TSC1 controls macrophage polarization to prevent inflammatory disease. Nat. Commun. 5, 4696 (2014).
Byles, V. et al. The TSC–mTOR pathway regulates macrophage polarization. Nat. Commun. 4, 2834 (2013).
Marcais, A. et al. The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the development and activation of NK cells. Nat. Immunol. 15, 749–757 (2014). This study shows that the proliferation and cytotoxicity of NK cells depend on activation of mTOR by high doses of IL-15.
Lelouard, H. et al. Regulation of translation is required for dendritic cell function and survival during activation. J. Cell Biol. 179, 1427–1439 (2007).
Ivanov, S. S. & Roy, C. R. Pathogen signatures activate a ubiquitination pathway that modulates the function of the metabolic checkpoint kinase mTOR. Nat. Immunol. 14, 1219–1228 (2013). This study shows that inhibition of mTOR in macrophages limits translation of low-abundance anti-inflammatory cytokines and creates a bias towards pro-inflammatory responses.
Everts, B. et al. TLR-driven early glycolytic reprogramming via the kinases TBK1–IKKɛ supports the anabolic demands of dendritic cell activation. Nat. Immunol. 15, 323–332 (2014).
Hsieh, A. C. et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 485, 55–61 (2012).
Jovanovic, M. et al. Dynamic profiling of the protein life cycle in response to pathogens. Science 347, 1259038 (2015).
Pollizzi, K. N. & Powell, J. D. Integrating canonical and metabolic signalling programmes in the regulation of T cell responses. Nat. Rev. Immunol. 14, 435–446 (2014).
O'Neill, L. A. & Hardie, D. G. Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature 493, 346–355 (2013).
Masui, K., Cavenee, W. K. & Mischel, P. S. mTORC2 in the center of cancer metabolic reprogramming. Trends Endocrinol. Metab. 25, 364–373 (2014).
Inoki, K., Kim, J. & Guan, K. L. AMPK and mTOR in cellular energy homeostasis and drug targets. Annu. Rev. Pharmacol. Toxicol. 52, 381–400 (2012).
Masui, K. et al. mTOR complex 2 controls glycolytic metabolism in glioblastoma through FoxO acetylation and upregulation of c-Myc. Cell. Metab. 18, 726–739 (2013).
Jewell, J. L., Russell, R. C. & Guan, K. L. Amino acid signalling upstream of mTOR. Nat. Rev. Mol. Cell Biol. 14, 133–139 (2013).
Zhang, J. et al. A tuberous sclerosis complex signalling node at the peroxisome regulates mTORC1 and autophagy in response to ROS. Nat. Cell Biol. 15, 1186–1196 (2013).
Thomas, J. D. et al. Rab1A is an mTORC1 activator and a colorectal oncogene. Cancer Cell 26, 754–769 (2014).
Roberts, D. J., Tan-Sah, V. P., Ding, E. Y., Smith, J. M. & Miyamoto, S. Hexokinase-II positively regulates glucose starvation-induced autophagy through TORC1 inhibition. Mol. Cell 53, 521–533 (2014).
Haller, J. F., Krawczyk, S. A., Gostilovitch, L., Corkey, B. E. & Zoeller, R. A. Glucose-6-phosphate isomerase deficiency results in mTOR activation, failed translocation of lipin 1α to the nucleus and hypersensitivity to glucose: implications for the inherited glycolytic disease. Biochim. Biophys. Acta 1812, 1393–1402 (2011).
Foster, D. A., Salloum, D., Menon, D. & Frias, M. A. Phospholipase D and the maintenance of phosphatidic acid levels for regulation of mammalian target of rapamycin (mTOR). J. Biol. Chem. 289, 22583–22588 (2014).
Laplante, M. & Sabatini, D. M. Regulation of mTORC1 and its impact on gene expression at a glance. J. Cell Sci. 126, 1713–1719 (2013).
Chen, C. et al. TSC–mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species. J. Exp. Med. 205, 2397–2408 (2008).
Wang, Y. et al. Tuberous sclerosis 1 (Tsc1)-dependent metabolic checkpoint controls development of dendritic cells. Proc. Natl Acad. Sci. USA 110, E4894–E4903 (2013).
Pan, H., O'Brien, T. F., Zhang, P. & Zhong, X. P. The role of tuberous sclerosis complex 1 in regulating innate immunity. J. Immunol. 188, 3658–3666 (2012).
Amiel, E. et al. Inhibition of mechanistic target of rapamycin promotes dendritic cell activation and enhances therapeutic autologous vaccination in mice. J. Immunol. 189, 2151–2158 (2012).
Krawczyk, C. M. et al. Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Blood 115, 4742–4749 (2010).
Everts, B. et al. Commitment to glycolysis sustains survival of NO-producing inflammatory dendritic cells. Blood 120, 1422–1431 (2012).
Amiel, E. et al. Mechanistic target of rapamycin inhibition extends cellular lifespan in dendritic cells by preserving mitochondrial function. J. Immunol. 193, 2821–2830 (2014). In this paper, the authors demonstrate that the mTOR-induced production of NO poisons mitochondrial respiration and necessitates an increase in aerobic glycolysis for survival in mouse but not human DCs.
Pantel, A. et al. Direct type I IFN but not MDA5/TLR3 activation of dendritic cells is required for maturation and metabolic shift to glycolysis after poly IC stimulation. PLoS Biol. 12, e1001759 (2014).
Nizet, V. & Johnson, R. S. Interdependence of hypoxic and innate immune responses. Nat. Rev. Immunol. 9, 609–617 (2009).
Quintin, J., Cheng, S. C., van der Meer, J. W. & Netea, M. G. Innate immune memory: towards a better understanding of host defense mechanisms. Curr. Opin. Immunol. 29, 1–7 (2014).
Cheng, S. C. et al. mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity. Science 345, 1250684 (2014).
Ferreira, G. B. et al. Vitamin D3 induces tolerance in human dendritic cells by activation of intracellular metabolic pathways. Cell Rep. 10, 711–725 (2015). References 44 and 45 demonstrate that mTOR-mediated glycolysis in myeloid immune cells triggers either tolerance or enhanced restimulation potential depending on the context.
Moon, J. S. et al. mTORC1-induced HK1-dependent glycolysis regulates NLRP3 inflammasome activation. Cell Rep. 12, 102–115 (2015).
Donnelly, R. P. et al. mTORC1-dependent metabolic reprogramming is a prerequisite for NK cell effector function. J. Immunol. 193, 4477–4484 (2014).
van de Laar, L. et al. PI3K–PKB hyperactivation augments human plasmacytoid dendritic cell development and function. Blood 120, 4982–4991 (2012).
Hackstein, H. et al. Rapamycin inhibits IL-4-induced dendritic cell maturation in vitro and dendritic cell mobilization and function in vivo. Blood 101, 4457–4463 (2003).
Scheffler, J. M. et al. LAMTOR2 regulates dendritic cell homeostasis through FLT3-dependent mTOR signalling. Nat. Commun. 5, 5138 (2014).
Kellersch, B. & Brocker, T. Langerhans cell homeostasis in mice is dependent on mTORC1 but not mTORC2 function. Blood 121, 298–307 (2013).
Sparber, F. et al. The late endosomal adaptor molecule p14 (LAMTOR2) represents a novel regulator of Langerhans cell homeostasis. Blood 123, 217–227 (2014).
Macedo, C. et al. Rapamycin augments human DC IL-12p70 and IL-27 secretion to promote allogeneic Type 1 polarization modulated by NK cells. Am. J. Transplant. 13, 2322–2333 (2013).
Wang, H. et al. Convergence of the mammalian target of rapamycin complex 1- and glycogen synthase kinase 3-β-signaling pathways regulatesthe innate inflammatory response. J. Immunol. 186, 5217–5226 (2011).
Yang, C. S. et al. Intracellular network of phosphatidylinositol 3-kinase, mammalian target of the rapamycin/70 kDa ribosomal S6 kinase 1, and mitogen-activated protein kinases pathways for regulating mycobacteria-induced IL-23 expression in human macrophages. Cell. Microbiol. 8, 1158–1171 (2006).
Gallon, L. et al. Cellular and molecular immune profiles in renal transplant recipients after conversion from tacrolimus to sirolimus. Kidney Int. 87, 828–838 (2014).
Brouard, S. et al. Comparative transcriptional and phenotypic peripheral blood analysis of kidney recipients under cyclosporin A or sirolimus monotherapy. Am. J. Transplant. 10, 2604–2614 (2010).
Foldenauer, M. E., McClellan, S. A., Berger, E. A. & Hazlett, L. D. Mammalian target of rapamycin regulates IL-10 and resistance to Pseudomonas aeruginosa corneal infection. J. Immunol. 190, 5649–5658 (2013).
Ohtani, M. et al. Cutting edge: mTORC1 in intestinal CD11c+ CD11b+ dendritic cells regulates intestinal homeostasis by promoting IL-10 production. J. Immunol. 188, 4736–4740 (2012).
Luo, L. et al. Rab8a interacts directly with PI3Kγ to modulate TLR4-driven PI3K and mTOR signalling. Nat. Commun. 5, 4407 (2014).
Pan, H. et al. Critical role of the tumor suppressor tuberous sclerosis complex 1 in dendritic cell activation of CD4 T cells by promoting MHC class II expression via IRF4 and CIITA. J. Immunol. 191, 699–707 (2013).
Brown, J., Wang, H., Suttles, J., Graves, D. T. & Martin, M. Mammalian target of rapamycin complex 2 (mTORC2) negatively regulates Toll-like receptor 4-mediated inflammatory response via FoxO1. J. Biol. Chem. 286, 44295–44305 (2011). This is the first demonstration that mTORC2 negatively regulates IL-12 production in DCs by inhibiting the activation of FOXO1.
Festuccia, W. T., Pouliot, P., Bakan, I., Sabatini, D. M. & Laplante, M. Myeloid-specific Rictor deletion induces M1 macrophage polarization and potentiates in vivo pro-inflammatory response to lipopolysaccharide. PLoS ONE 9, e95432 (2014).
Raich-Regue, D. et al. mTORC2 deficiency in myeloid dendritic cells enhances their allogeneic Th1 and Th17 stimulatory ability after TLR4 ligation in vitro and in vivo. J. Immunol. 194, 4767–4776 (2015).
Fan, W. et al. FoxO1 regulates Tlr4 inflammatory pathway signalling in macrophages. EMBO J. 29, 4223–4236 (2010).
Jorgensen, P. F. et al. Sirolimus interferes with the innate response to bacterial products in human whole blood by attenuation of IL-10 production. Scand. J. Immunol. 53, 184–191 (2001).
Mercalli, A. et al. Rapamycin unbalances the polarization of human macrophages to M1. Immunology 140, 179–190 (2013).
van den Bosch, M. W., Palsson-Mcdermott, E., Johnson, D. S. & O'Neill, L. A. LPS induces the degradation of programmed cell death protein 4 (PDCD4) to release Twist2, activating c-Maf transcription to promote interleukin-10 production. J. Biol. Chem. 289, 22980–22990 (2014).
Wang, G. Y. et al. Rapamycin-treated mature dendritic cells have a unique cytokine secretion profile and impaired allostimulatory capacity. Transpl. Int. 22, 1005–1016 (2009).
Macedo, C., Turquist, H., Metes, D. & Thomson, A. W. Immunoregulatory properties of rapamycin-conditioned monocyte-derived dendritic cells and their role in transplantation. Transplant. Res. 1, 16 (2012).
Thomson, A. W., Turnquist, H. R. & Raimondi, G. Immunoregulatory functions of mTOR inhibition. Nat. Rev. Immunol. 9, 324–337 (2009).
López-Pelaéz, M. et al. Cot/tpl2–MKK1/2–Erk1/2 controls mTORC1-mediated mRNA translation in Toll-like receptor-activated macrophages. Mol. Biol. Cell 23, 2982–2992 (2012).
Schott, J. et al. Translational regulation of specific mRNAs controls feedback inhibition and survival during macrophage activation. PLoS Genet. 10, e1004368 (2014).
Colina, R. et al. Translational control of the innate immune response through IRF-7. Nature 452, 323–328 (2008).
Cao, W. et al. Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K–mTOR–p70S6K pathway. Nat. Immunol. 9, 1157–1164 (2008). References 74 and 75 show for the first time that expression of type I IFNs is controlled by the mTOR pathway through activation and translation of IRF7.
Jaramillo, M. et al. Leishmania repression of host translation through mTOR cleavage is required for parasite survival and infection. Cell Host Microbe 9, 331–341 (2011).
Fekete, T. et al. The antiviral immune response in human conventional dendritic cells is controlled by the mammalian target of rapamycin. J. Leukoc. Biol. 96, 579–589 (2014).
Murray, P. J. et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41, 14–20 (2014).
Shaul, M. E., Bennett, G., Strissel, K. J., Greenberg, A. S. & Obin, M. S. Dynamic, M2-like remodeling phenotypes of CD11c+ adipose tissue macrophages during high-fat diet-induced obesity in mice. Diabetes 59, 1171–1181 (2010).
Chawla, A., Nguyen, K. D. & Goh, Y. P. Macrophage-mediated inflammation in metabolic disease. Nat. Rev. Immunol. 11, 738–749 (2011).
Weisser, S. B. et al. Alternative activation of macrophages by IL-4 requires SHIP degradation. Eur. J. Immunol. 41, 1742–1753 (2011).
Yue, S. et al. Myeloid PTEN deficiency protects livers from ischemia reperfusion injury by facilitating M2 macrophage differentiation. J. Immunol. 192, 5343–5353 (2014).
Sahin, E. et al. Macrophage PTEN regulates expression and secretion of arginase I modulating innate and adaptive immune responses. J. Immunol. 193, 1717–1727 (2014).
Chen, W. et al. Macrophage-induced tumor angiogenesis is regulated by the TSC2–mTOR pathway. Cancer Res. 72, 1363–1372 (2012).
Rocher, C. & Singla, D. K. SMAD–PI3K–Akt–mTOR pathway mediates BMP-7 polarization of monocytes into M2 macrophages. PLoS ONE 8, e84009 (2013).
Fang, C. et al. Tsc1 is a critical regulator of macrophage survival and function. Cell Physiol. Biochem. 36, 1406–1418 (2015).
Jiang, H., Westerterp, M., Wang, C., Zhu, Y. & Ai, D. Macrophage mTORC1 disruption reduces inflammation and insulin resistance in obese mice. Diabetologia 57, 2393–2404 (2014).
Arranz, A. et al. Akt1 and Akt2 protein kinases differentially contribute to macrophage polarization. Proc. Natl Acad. Sci. USA 109, 9517–9522 (2012). In this study, the authors identify opposing functions of the isoforms AKT1 and AKT2 in macrophage polarization, highlighting the complexity of the PI3K–AKT–mTOR pathway.
Babaev, V. R. et al. Macrophage deficiency of Akt2 reduces atherosclerosis in Ldlr null mice. J. Lipid Res. 55, 2296–2308 (2014).
Kawano, Y. et al. Loss of Pdk1–Foxo1 signaling in myeloid cells predisposes to adipose tissue inflammation and insulin resistance. Diabetes 61, 1935–1948 (2012).
Zhu, Y. P., Brown, J. R., Sag, D., Zhang, L. & Suttles, J. Adenosine 5′-monophosphate-activated protein kinase regulates IL-10-mediated anti-inflammatory signaling pathways in macrophages. J. Immunol. 194, 548–594 (2014).
Galic, S. et al. Hematopoietic AMPK β1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity. J. Clin. Invest. 121, 4903–4915 (2011).
Galván-Peña, S. & O'Neill, L. A. Metabolic reprograming in macrophage polarization. Front. Immunol. 5, 420 (2014).
Tan, Z. et al. Pyruvate dehydrogenase kinase 1 participates in macrophage polarization via regulating glucose metabolism. J. Immunol. 194, 6082–6089 (2015).
Pello, O. M. et al. Role of c-MYC in alternative activation of human macrophages and tumor-associated macrophage biology. Blood 119, 411–421 (2012).
Nasi, A. et al. Dendritic cell reprogramming by endogenously produced lactic acid. J. Immunol. 191, 3090–3099 (2013).
Colegio, O. R. et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513, 559–563 (2014). References 96 and 97 show that lactic acid, an end product of aerobic glycolysis, produced by DCs or tumour cells can directly influence innate immune responses.
Chazaud, B. Macrophages: supportive cells for tissue repair and regeneration. Immunobiology 219, 172–178 (2014).
Bleriot, C. et al. Liver-resident macrophage necroptosis orchestrates type 1 microbicidal inflammation and type-2-mediated tissue repair during bacterial infection. Immunity 42, 145–158 (2015).
Deretic, V. Autophagy as an innate immunity paradigm: expanding the scope and repertoire of pattern recognition receptors. Curr. Opin. Immunol. 24, 21–31 (2012).
Narita, M. et al. Spatial coupling of mTOR and autophagy augments secretory phenotypes. Science 332, 966–970 (2011).
Zhang, X. et al. CaMKIV-dependent preservation of mTOR expression is required for autophagy during lipopolysaccharide-induced inflammation and acute kidney injury. J. Immunol. 193, 2405–2415 (2014).
Yu, L. et al. Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature 465, 942–946 (2010).
Gutierrez, M. G. et al. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119, 753–766 (2004).
Wang, J. et al. MicroRNA-155 promotes autophagy to eliminate intracellular mycobacteria by targeting Rheb. PLoS Pathog. 9, e1003697 (2013).
Birmingham, C. L., Smith, A. C., Bakowski, M. A., Yoshimori, T. & Brumell, J. H. Autophagy controls Salmonella infection in response to damage to the Salmonella-containing vacuole. J. Biol. Chem. 281, 11374–11383 (2006).
Yuan, K. et al. Autophagy plays an essential role in the clearance of Pseudomonas aeruginosa by alveolar macrophages. J. Cell Sci. 125, 507–515 (2012).
Owen, K. A., Meyer, C. B., Bouton, A. H. & Casanova, J. E. Activation of focal adhesion kinase by Salmonella suppresses autophagy via an Akt/mTOR signaling pathway and promotes bacterial survival in macrophages. PLoS Pathog. 10, e1004159 (2014).
Blanchet, F. P. et al. Human immunodeficiency virus-1 inhibition of immunoamphisomes in dendritic cells impairs early innate and adaptive immune responses. Immunity 32, 654–669 (2010).
Sergin, I. & Razani, B. Self-eating in the plaque: what macrophage autophagy reveals about atherosclerosis. Trends Endocrinol. Metab. 25, 225–234 (2014).
Le Guezennec, X. et al. Wip1-dependent regulation of autophagy, obesity, and atherosclerosis. Cell. Metab. 16, 68–80 (2012).
Zhai, C. et al. Selective inhibition of PI3K/Akt/mTOR signaling pathway regulates autophagy of macrophage and vulnerability of atherosclerotic plaque. PLoS ONE 9, e90563 (2014).
Ai, D. et al. Disruption of mammalian target of rapamycin complex 1 in macrophages decreases chemokine gene expression and atherosclerosis. Circ. Res. 114, 1576–1584 (2014).
Chen, W. Q. et al. Oral rapamycin attenuates inflammation and enhances stability of atherosclerotic plaques in rabbits independent of serum lipid levels. Br. J. Pharmacol. 156, 941–951 (2009).
Mintern, J. D., Macri, C. & Villadangos, J. A. Modulation of antigen presentation by intracellular trafficking. Curr. Opin. Immunol. 34, 16–21 (2015).
Jagannath, C. et al. Autophagy enhances the efficacy of BCG vaccine by increasing peptide presentation in mouse dendritic cells. Nat. Med. 15, 267–276 (2009). This study is the first to demonstrate that mTOR inhibition enhances the efficacy of DCs in an autologous vaccination protocol.
Hackstein, H., Taner, T., Logar, A. J. & Thomson, A. W. Rapamycin inhibits macropinocytosis and mannose receptor-mediated endocytosis by bone marrow-derived dendritic cells. Blood 100, 1084–1087 (2002).
Araki, K., Ellebedy, A. H. & Ahmed, R. TOR in the immune system. Curr. Opin. Cell Biol. 23, 707–715 (2011).
Rosborough, B. R. et al. Murine dendritic cell rapamycin-resistant and rictor-independent mTOR controls IL-10, B7-H1, and regulatory T-cell induction. Blood 121, 3619–3630 (2013).
Taner, T., Hackstein, H., Wang, Z., Morelli, A. E. & Thomson, A. W. Rapamycin-treated, alloantigen-pulsed host dendritic cells induce Ag-specific T cell regulation and prolong graft survival. Am. J. Transplant. 5, 228–236 (2005).
Sordi, V. et al. Differential effects of immunosuppressive drugs on chemokine receptor CCR7 in human monocyte-derived dendritic cells: selective upregulation by rapamycin. Transplantation 82, 826–834 (2006).
Sinclair, L. V. et al. Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking. Nat. Immunol. 9, 513–521 (2008).
Baetta, R. et al. Everolimus inhibits monocyte/macrophage migration in vitro and their accumulation in carotid lesions of cholesterol-fed rabbits. J. Pharmacol. Exp. Ther. 328, 419–425 (2009).
Perino, A. et al. TGR5 reduces macrophage migration through mTOR-induced C/EBPβ differential translation. J. Clin. Invest. 124, 5425–5436 (2014).
Fox, R. et al. PSGL-1 and mTOR regulate translation of ROCK-1 and physiological functions of macrophages. EMBO J. 26, 505–515 (2007). This study highlights the importance of translational regulation of gene expression for effector responses in macrophages.
Kolaczkowska, E. & Kubes, P. Neutrophil recruitment and function in health and inflammation. Nat. Rev. Immunol. 13, 159–175 (2013).
Liu, L. & Parent, C. A. Review series: TOR kinase complexes and cell migration. J. Cell Biol. 194, 815–824 (2011).
He, Y. et al. Mammalian target of rapamycin and Rictor control neutrophil chemotaxis by regulating Rac/Cdc42 activity and the actin cytoskeleton. Mol. Biol. Cell 24, 3369–3380 (2013).
Liu, L., Das, S., Losert, W. & Parent, C. A. mTORC2 regulates neutrophil chemotaxis in a cAMP- and RhoA-dependent fashion. Dev. Cell 19, 845–857 (2010). The authors of this paper uncover an important role of mTORC2 in neutrophil polarization and directed migration.
Chen, J., Tang, H., Hay, N., Xu, J. & Ye, R. D. Akt isoforms differentially regulate neutrophil functions. Blood 115, 4237–4246 (2010).
Liu, L., Gritz, D. & Parent, C. A. PKCβII acts downstream of chemoattractant receptors and mTORC2 to regulate cAMP production and myosin II activity in neutrophils. Mol. Biol. Cell 25, 1446–1457 (2014).
Gomez-Cambronero, J. Rapamycin inhibits GM-CSF-induced neutrophil migration. FEBS Lett. 550, 94–100 (2003).
Frondorf, K., Henkels, K. M., Frohman, M. A. & Gomez-Cambronero, J. Phosphatidic acid is a leukocyte chemoattractant that acts through S6 kinase signaling. J. Biol. Chem. 285, 15837–15847 (2010).
Fernández, N., González, A., Valera, I., Alonso, S. & Crespo, M. S. Mannan and peptidoglycan induce COX-2 protein in human PMN via the mammalian target of rapamycin. Eur. J. Immunol. 37, 2572–2582 (2007).
Wall, M. et al. Translational control of c-MYC by rapamycin promotes terminal myeloid differentiation. Blood 112, 2305–2317 (2008).
Lindemann, S. W. et al. Neutrophils alter the inflammatory milieu by signal-dependent translation of constitutive messenger RNAs. Proc. Natl Acad. Sci. USA 101, 7076–7081 (2004).
Kaplanski, G., Marin, V., Montero-Julian, F., Mantovani, A. & Farnarier, C. IL-6: a regulator of the transition from neutrophil to monocyte recruitment during inflammation. Trends Immunol. 24, 25–29 (2003).
McInturff, A. M. et al. Mammalian target of rapamycin regulates neutrophil extracellular trap formation via induction of hypoxia-inducible factor 1 α. Blood 120, 3118–3125 (2012).
Itakura, A. & McCarty, O. J. Pivotal role for the mTOR pathway in the formation of neutrophil extracellular traps via regulation of autophagy. Am. J. Physiol. Cell Physiol. 305, C348–C354 (2013). References 138 and 139 demonstrate that mTOR regulates NET formation.
Gupta, A. K., Giaglis, S., Hasler, P. & Hahn, S. Efficient neutrophil extracellular trap induction requires mobilization of both intracellular and extracellular calcium pools and is modulated by cyclosporine A. PLoS ONE 9, e97088 (2014).
Remijsen, Q. et al. Neutrophil extracellular trap cell death requires both autophagy and superoxide generation. Cell Res. 21, 290–304 (2011).
Vitiello, D., Neagoe, P. E., Sirois, M. G. & White, M. Effect of everolimus on the immunomodulation of the human neutrophil inflammatory response and activation. Cell. Mol. Immunol. 12, 40–52 (2014).
Hua, W. et al. Rapamycin inhibition of eosinophil differentiation attenuates allergic airway inflammation in mice. Respirology http:/dx.doi.org/10.1111/resp.12554, (2015).
Voehringer, D. Protective and pathological roles of mast cells and basophils. Nat. Rev. Immunol. 13, 362–375 (2013).
Kim, M. S., Kuehn, H. S., Metcalfe, D. D. & Gilfillan, A. M. Activation and function of the mTORC1 pathway in mast cells. J. Immunol. 180, 4586–4595 (2008).
Kuehn, H. S., Jung, M. Y., Beaven, M. A., Metcalfe, D. D. & Gilfillan, A. M. Prostaglandin E2 activates and utilizes mTORC2 as a central signaling locus for the regulation of mast cell chemotaxis and mediator release. J. Biol. Chem. 286, 391–402 (2011).
Smrz, D. et al. mTORC1 and mTORC2 differentially regulate homeostasis of neoplastic and non-neoplastic human mast cells. Blood 118, 6803–6813 (2011).
Shin, J., Pan, H. & Zhong, X. P. Regulation of mast cell survival and function by tuberous sclerosis complex 1. Blood 119, 3306–3314 (2012).
Smrz, D. et al. Rictor negatively regulates high-affinity receptors for IgE-induced mast cell degranulation. J. Immunol. 193, 5924–5932 (2014).
Shi, F. D., Ljunggren, H. G., La Cava, A. & Van Kaer, L. Organ-specific features of natural killer cells. Nat. Rev. Immunol. 11, 658–671 (2011).
Nandagopal, N., Ali, A. K., Komal, A. K. & Lee, S. H. The critical role of IL-15–PI3K–mTOR pathway in natural killer cell effector functions. Front. Immunol. 5, 187 (2014).
Yang, M. et al. PDK1 orchestrates early NK cell development through induction of E4BP4 expression and maintenance of IL-15 responsiveness. J. Exp. Med. 212, 253–265 (2015).
Wai, L. E., Fujiki, M., Takeda, S., Martinez, O. M. & Krams, S. M. Rapamycin, but not cyclosporine or FK506, alters natural killer cell function. Transplantation 85, 145–149 (2008).
Salmond, R. J. et al. IL-33 induces innate lymphoid cell-mediated airway inflammation by activating mammalian target of rapamycin. J. Allergy Clin. Immunol. 130, 1159–1166.e6 (2012).
Visvikis, O. et al. Innate host defense requires TFEB-mediated transcription of cytoprotective and antimicrobial genes. Immunity 40, 896–909 (2014).
Lamming, D. W. et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335, 1638–1643 (2012).
Touzot, M., Soulillou, J. P. & Dantal, J. Mechanistic target of rapamycin inhibitors in solid organ transplantation: from benchside to clinical use. Curr. Opin. Organ. Transplant 17, 626–633 (2012).
Toyota, T., Shiomi, H., Morimoto, T. & Kimura, T. Meta-analysis of long-term clinical outcomes of everolimus-eluting stents. Am. J. Cardiol. 116, 187–194 (2015).
Chiarini, F., Evangelisti, C., McCubrey, J. A. & Martelli, A. M. Current treatment strategies for inhibiting mTOR in cancer. Trends Pharmacol. Sci. 36, 124–135 (2015).
Günzl, P. & Schabbauer, G. Recent advances in the genetic analysis of PTEN and PI3K innate immune properties. Immunobiology 213, 759–765 (2008).
Brognard, J., Sierecki, E., Gao, T. & Newton, A. C. PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms. Mol. Cell 25, 917–931 (2007).
Neuman, N. A. & Henske, E. P. Non-canonical functions of the tuberous sclerosis complex–Rheb signalling axis. EMBO Mol. Med. 3, 189–200 (2011).
Katholnig, K. et al. p38α senses environmental stress to control innate immune responses via mechanistic target of rapamycin. J. Immunol. 190, 1519–1527 (2013).
McGuire, V. A. et al. Cross talk between the Akt and p38α pathways in macrophages downstream of Toll-like receptor signaling. Mol. Cell. Biol. 33, 4152–4165 (2013).
Ma, L., Chen, Z., Erdjument-Bromage, H., Tempst, P. & Pandolfi, P. P. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 121, 179–193 (2005).
Acknowledgements
This work was supported by grants from the Austrian Science Fund (FWF; grant FWF-P27701-B20), the Else Kröner-Fresenius-Stiftung (P2013_A149) and the Herzfelder'sche Familienstiftung. The authors apologize to those colleagues whose work has not been cited owing to space constraints.
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Glossary
- mTOR complex 1
-
(mTORC1). A complex consisting of: mammalian target of rapamycin (mTOR), which is a serine/threonine kinase; regulatory-associated protein of mTOR (RAPTOR); proline-rich AKT1 substrate of 40 kDa (PRAS40), which is an mTORC1 inhibitor; mLST8 (also known as GβL), which is of unknown function; and DEP domain-containing mTOR-interacting protein (DEPTOR), which is an mTOR inhibitor.
- mTORC2
-
A complex composed of: mammalian target of rapamycin (mTOR), mLST8 and the adaptor proteins rapamycin-insensitive companion of mTOR (RICTOR) and stress-activated MAP kinase-interacting protein 1 (SIN1).
- Tuberous sclerosis 1
-
(TSC1). TSC1 forms a heterodimeric complex with TSC2. The TSC1–TSC2 complex actively inhibits mammalian target of rapamycin complex 1 (mTORC1) in unstimulated cells. Stimulation promotes AKT-dependent phosphorylation and inactivation of the complex. TSC1–TSC2 seems to be a positive regulator of mTORC2.
- Pyruvate
-
The end product of glycolysis, which can be further metabolized to lactate in a process known as aerobic glycolysis (also known as the Warburg effect). Pyruvate can also be oxidized in the mitochondria through the tricarboxylic acid (TCA) cycle followed by oxidative phosphorylation to generate ATP.
- Langerhans cells
-
A specialized subset of dendritic cells that seed the epidermal layer of the skin.
- M1 and M2 macrophage subsets
-
Macrophages display considerable plasticity and can change their function in response to local environmental stimuli. M1 (or classically activated) macrophages mediate defence against various pathogens and tumours and contribute to chronic inflammatory diseases and autoimmunity. M2 (or alternatively activated) macrophages are required for defence against parasitic infections, to promote the resolution of inflammation, and to initiate tissue repair, and they are also implicated in promoting tumour growth.
- STAT6
-
(Signal transducer and activator of transcription 6). A transcription factor that is important for M2 macrophage polarization after stimulation with interleukin-4 (IL-4) or IL-13. STAT6 regulates many M2 macrophage-associated genes, such as those encoding arginase 1, CD206, resistin-like-α and chitinase-like protein 3 (also known as YM1).
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Weichhart, T., Hengstschläger, M. & Linke, M. Regulation of innate immune cell function by mTOR. Nat Rev Immunol 15, 599–614 (2015). https://doi.org/10.1038/nri3901
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DOI: https://doi.org/10.1038/nri3901
