Key Points
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The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth, proliferation, survival and autophagy in a cell-type-specific manner
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mTOR forms two interacting complexes, mTORC1 and mTORC2
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mTORC1 drives the proinflammatory expansion of T helper (TH) type 1, TH17, and CD4−CD8− double-negative T cells, which collectively orchestrate the pathogenesis of autoimmune diseases
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mTORC1 contributes to erosive arthritis by mediating the proliferation of fibroblasts-like synoviocytes and osteoclasts, and contributes to osteoarthritis by restraining autophagy in chondrocytes
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Blockade of the mTOR pathway offers new treatments and prevention strategies for rheumatic diseases
Abstract
Mechanistic target of rapamycin (mTOR, also known as mammalian target of rapamycin) is a ubiquitous serine/threonine kinase that regulates cell growth, proliferation and survival. These effects are cell-type-specific, and are elicited in response to stimulation by growth factors, hormones and cytokines, as well as to internal and external metabolic cues. Rapamycin was initially developed as an inhibitor of T-cell proliferation and allograft rejection in the organ transplant setting. Subsequently, its molecular target (mTOR) was identified as a component of two interacting complexes, mTORC1 and mTORC2, that regulate T-cell lineage specification and macrophage differentiation. mTORC1 drives the proinflammatory expansion of T helper (TH) type 1, TH17, and CD4−CD8− (double-negative, DN) T cells. Both mTORC1 and mTORC2 inhibit the development of CD4+CD25+FoxP3+ T regulatory (TREG) cells and, indirectly, mTORC2 favours the expansion of T follicular helper (TFH) cells which, similarly to DN T cells, promote B-cell activation and autoantibody production. In contrast to this proinflammatory effect of mTORC2, mTORC1 favours, to some extent, an anti-inflammatory macrophage polarization that is protective against infections and tissue inflammation. Outside the immune system, mTORC1 controls fibroblast proliferation and chondrocyte survival, with implications for tissue fibrosis and osteoarthritis, respectively. Rapamycin (which primarily inhibits mTORC1), ATP-competitive, dual mTORC1/mTORC2 inhibitors and upstream regulators of the mTOR pathway are being developed to treat autoimmune, hyperproliferative and degenerative diseases. In this regard, mTOR blockade promises to increase life expectancy through treatment and prevention of rheumatic diseases.
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References
Vezina, C., Kudelski, A. & Sehgal, S. N. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J. Antibiot. (Tokyo) 28, 721–726 (1975).
Sehgal, S. N. & Bansback, C. C. Rapamycin: in vitro profile of a new immunosuppressive macrolide. Ann. NY Acad. Sci. 685, 58–67 (1993).
Collier, D. S. J. et al. Rapamycin in experimental renal allografts in dogs and pigs. Transplant. Proc. 22, 1674–1675 (1990).
Calne, R. Y. et al. Rapamycin for immunosuppression in organ allografting. Lancet 334, 227 (1989).
Warner, L. M., Adams, L. M. & Sehgal, S. N. Rapamycin prolongs survival and arrests pathophysiologic changes in murine systemic lupus erythematosus. Arthritis Rheum. 37, 289–297 (1994).
Fernandez, D., Bonilla, E., Mirza, N., Niland, B. & Perl, A. Rapamycin reduces disease activity and normalizes T-cell activation-induced calcium fluxing in patients with systemic lupus erythematosus. Arthritis Rheum. 54, 2983–2988 (2006).
Cejka, D. et al. Mammalian target of rapamycin signaling is crucial for joint destruction in experimental arthritis and is activated in osteoclasts from patients with rheumatoid arthritis. Arthritis Rheum. 62, 2294–2302 (2010).
Bruyn, G. A. W. et al. Everolimus in patients with rheumatoid arthritis receiving concomitant methotrexate: a 3-month, double-blind, randomised, placebo-controlled, parallel-group, proof-of-concept study. Ann. Rheum. Dis. 67, 1090–1095 (2008).
Foroncewicz, B., Mucha, K., Pà czek, L., Chmura, A. & Rowin´ski, W. Efficacy of rapamycin in patient with juvenile rheumatoid arthritis. Transpl. Int. 18, 366–368 (2005).
Shah, M. et al. A rapamycin-binding protein polymer nanoparticle shows potent therapeutic activity in suppressing autoimmune dacryoadenitis in a mouse model of Sjögren's syndrome. J. Control. Release 171, 269–279 (2013).
Ponticos, M. et al. Failed degradation of JunB contributes to overproduction of type I collagen and development of dermal fibrosis in patients with systemic sclerosis. Arthritis Rheumatol. 67, 243–253 (2015).
Tamaki, Z. et al. Effects of the immunosuppressant rapamycin on the expression of human α2(I) collagen and matrix metalloproteinase 1 genes in scleroderma dermal fibroblasts. J. Dermatol. Sci. 74, 251–259 (2014).
Yoshizaki, A. et al. Treatment with rapamycin prevents fibrosis in tight-skin and bleomycin-induced mouse models of systemic sclerosis. Arthritis Rheum. 62, 2476–2487 (2010).
Chen, C. et al. mTOR inhibition rescues osteopenia in mice with systemic sclerosis. J. Exp. Med. 212, 73–91 (2015).
Su, T. I. et al. Rapamycin versus methotrexate in early diffuse systemic sclerosis: results from a randomized, single-blind pilot study. Arthritis Rheum. 60, 3821–3830 (2009).
Terasawa, A. et al. Sirolimus-eluting stent implantation for ostial stenosis of left main coronary artery after Bentall operation in aortitis syndrome. J. Cardiol. 55, 147–150 (2010).
Furukawa, Y. et al. Sirolimus-eluting stent for in-stent restenosis of left main coronary artery in Takayasu arteritis. Circ. J. 69, 752–755 (2005).
Koening, C. L., Hernandez-Rodriguez, J., Molloy, E. S., Clark, T. M. & Hoffman, G. S. Limited utility of rapamycin in severe, refractory Wegener's granulomatosis. J. Rheumatol. 36, 116–119 (2009).
Constantinescu, A. R., Liang, M. & Laskow, D. A. Sirolimus lowers myeloperoxidase and p-ANCA titers in a pediatric patient before kidney transplantation. Am. J. Kidney Dis. 40, 407–410 (2002).
Lopez de Figueroa, P., Lotz, M. K., Blanco, F. J. & Carames, B. Autophagy activation and protection from mitochondrial dysfunction in human chondrocytes. Arthritis Rheum. 67, 966–976 (2015).
Chauvin, C. et al. Ribosomal protein S6 kinase activity controls the ribosome biogenesis transcriptional program. Oncogene 33, 474–483 (2014).
Gingras, A. C. et al. Regulation of 4E-BP1 phosphorylation: a novel two step mechanism. Genes Dev. 13, 1422–1437 (1999).
Kim, J. H., Yoon, M. S. & Chen, J. Signal transducer and activator of transcription 3 (STAT3) mediates amino acid inhibition of insulin signaling through serine 727 phosphorylation. J. Biol. Chem. 284, 35425–35432 (2009).
Nazio, F. et al. MTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function through AMBRA1 and TRAF6. Nat. Cell. Biol. 15, 406–416 (2013).
Alers, S., Loffler, A. S., Wesselborg, S. & Stork, B. Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol. Cell. Biol. 32, 2–11 (2012).
Zoncu, R. et al. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H+-ATPase. Science 334, 678–683 (2011).
Bar-Peled, L. et al. A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science 340, 1100–1106 (2013).
Sarbassov, D. D. & Sabatini, D. M. Redox regulation of the nutrient-sensitive raptor–mTOR pathway and complex. J. Biol. Chem. 280, 39505–39509 (2005).
Thedieck, K. et al. Inhibition of mTORC1 by astrin and stress granules prevents apoptosis in cancer cells. Cell 154, 859–874 (2013).
Fernandez, D. R. et al. Activation of mTOR controls the loss of TCRζ in lupus T cells through HRES-1/Rab4-regulated lysosomal degradation. J. Immunol. 182, 2063–2073 (2009).
Sonenberg, N. & Hinnebusch, A. G. Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 136, 731–745 (2009).
Sancak, Y. et al. The Rag GTPases bind Raptor and mediate amino acid signaling to mTORC1. Science 320, 1496–1501 (2008).
Desai, B. N., Myers, B. R. & Schreiber, S. L. FKBP12-rapamycin-associated protein associates with mitochondria and senses osmotic stress via mitochondrial dysfunction. Proc. Natl Acad. Sci. USA 99, 4319–4324 (2002).
Shor, B. et al. Requirement of the mTOR kinase for the regulation of Maf1 phosphorylation and control of RNA polymerase III-dependent transcription in cancer cells. J. Biol. Chem. 285, 15380–15392 (2010).
Tsang, C. K., Liu, H. & Zheng, X. S. mTOR binds to the promoters of RNA polymerase I- and III-transcribed genes. Cell Cycle 9, 953–957 (2010).
Ravikumar, B., Imarisio, S., Sarkar, S., O'Kane, C. J. & Rubinsztein, D. C. Rab5 modulates aggregation and toxicity of mutant huntingtin through macroautophagy in cell and fly models of Huntington disease. J. Cell. Sci. 121, 1649–1660 (2008).
Su, W. C. et al. Rab5 and class III phosphoinositide 3-kinase Vps34 are involved in hepatitis C virus NS4B-induced autophagy. J. Virol. 85, 10561–10571 (2011).
Jia, W., Pua, H. H., Li, Q. J. & He, Y. W. Autophagy regulates endoplasmic reticulum homeostasis and calcium mobilization in T lymphocytes. J. Immunol. 186, 1564–1574 (2011).
Gutierrez, M. G., Munafo, D. B., Beron, W. & Colombo, M. I. Rab7 is required for the normal progression of the autophagic pathway in mammalian cells. J. Cell Sci. 117, 2687–2697 (2004).
Stein, M. P., Feng, Y., Cooper, K. L., Welford, A. M. & Wandinger-Ness, A. Human VPS34 and p150 are Rab7 interacting partners. Traffic 4, 754–771 (2003).
Caza, T. N. et al. HRES-1/RAB4-mediated depletion of Drp1 impairs mitochondrial homeostasis and represents a target for treatment in SLE. Ann. Rheum. Dis. 73, 1887–1897 (2014).
Talaber, G. et al. HRES-1/Rab4 promotes the formation of LC3+ autophagosomes and the accumulation of mitochondria during autophagy. PLoS ONE 9, e84392 (2014).
Telarico, T. et al. HRES-1/Rab4 lupus susceptibility gene selectively regulates mammalian target of rapamycin complexes 1 and 2 in T lymphocytes. Arthritis Rheum. Abstr. 63 (Suppl. 10), 2358 (2011).
Chamberlain, M. D., Berry, T. R., Pastor, M. C. & Anderson, D. H. The p85α subunit of phosphatidylinositol 3′-kinase binds to and stimulates the GTPase activity of Rab proteins. J. Biol. Chem. 279, 48607–48614 (2004).
Chamberlain, M. D. et al. Disrupted RabGAP function of the p85 subunit of phosphatidylinositol 3-kinase results in cell transformation. J. Biol. Chem. 283, 15861–15868 (2008).
Chamberlain, M. D. et al. Deregulation of Rab5 and Rab4 proteins in p85R274A-expressing cells alters PDGFR trafficking. Cell. Signal. 22, 1562–1575 (2010).
Kausch, C. et al. Association of impaired phosphatidylinositol 3-kinase activity in GLUT1-containing vesicles with malinsertion of glucose transporters into the plasma membrane of fibroblasts from a patient with severe insulin resistance and clinical features of Werner syndrome. J. Clin. Endocrin. Metab. 85, 905–918 (2000).
Kim, S. G. et al. Metabolic stress controls mTORC1 lysosomal localization and dimerization by regulating the TTT-RUVBL1/2 complex. Mol. Cell 49, 172–185 (2013).
Honda, K. et al. Spatiotemporal regulation of MyD88–IRF-7 signalling for robust type-I interferon induction. Nature 434, 1035–1040 (2005).
Caro-Maldonado, A., Gerriets, V. A. & Rathmell, J. C. Matched and mismatched metabolic fuels in lymphocyte function. Semin. Immunol. 24, 405–413 (2012).
Delgoffe, G. M. et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat. Immunol. 12, 295–304 (2011).
Mercalli, A. et al. Rapamycin unbalances the polarization of human macrophages to M1. Immunology 140, 179–190 (2013).
Zhu, L. et al. TSC1 controls macrophage polarization to prevent inflammatory disease. Nat. Commun. 5, 4696 (2014).
Poglitsch, M. et al. CMV late phase-induced mTOR activation is essential for efficient virus replication in polarized human macrophages. Am. J. Transplant. 12, 1458–1468 (2012).
Vasheghani, F. et al. PPARγ deficiency results in severe, accelerated osteoarthritis associated with aberrant mTOR signalling in the articular cartilage. Ann. Rheum. Dis. 74, 569–578 (2015).
Garcia, R. J. et al. Attention deficit and hyperactivity disorder scores are elevated and respond to NAC treatment in patients with SLE. Arthritis Rheum. 65, 1313–1318 (2013).
Proud, C. G. Regulation of mammalian translation factors by nutrients. Eur. J. Biochem. 269, 5338–5349 (2002).
Duran, R. et al. Glutaminolysis activates Rag−mTORC1 signaling. Mol. Cell 47, 349–358 (2012).
Jewell, J. L. et al. Differential regulation of mTORC1 by leucine and glutamine. Science 347, 194–198 (2015).
Perl, A. et al. Comprehensive metabolome analyses reveal N-acetylcysteine-responsive accumulation of kynurenine in systemic lupus erythematosus: implications for activation of the mechanistic target of rapamycin. Metabolomics 11, 1157–1174 (2015).
Duvel, K. et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 39, 171–183 (2010).
Semenza, G. L. HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J. Clin. Invest. 123, 3664–3671 (2013).
Liu, G. et al. SIRT1 limits the function and fate of myeloid-derived suppressor cells in tumors by orchestrating HIF-1-α dependent glycolysis. Cancer Res. 74, 727–737 (2014).
Ben-Sahra, I., Howell, J. J., Asara, J. M. & Manning, B. D. Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. Science 339, 1323–1328 (2013).
Sun, Y. et al. Estradiol promotes pentose phosphate pathway addiction and cell survival via reactivation of Akt in mTORC1 hyperactive cells. Cell Death Dis. 5, e1231 (2014).
Taylor, S. S., Zhang, P., Steichen, J. M., Keshwani, M. M. & Kornev, A. P. PKA: lessons learned after twenty years. Biochim. Biophys. Acta 1834, 1271–1278 (2013).
de Joussineau, C. et al. mTOR pathway is activated by PKA in adrenocortical cells and participates in vivo to apoptosis resistance in primary pigmented nodular adrenocortical disease (PPNAD). Hum. Mol. Genet. 23, 5418–5428 (2014).
Yoo, S. E. et al. Gpx4 ablation in adult mice results in a lethal phenotype accompanied by neuronal loss in brain. Free Radic. Biol. Med. 52, 1820–1827 (2012).
Xie, J. et al. CAMP inhibits mammalian target of rapamycin complex-1 and -2 (mTORC1 and 2) by promoting complex dissociation and inhibiting mTOR kinase activity. Cell. Signal. 23, 1927–1935 (2011).
Lai, Z.-W. et al. N-acetylcysteine reduces disease activity by blocking mTOR in T cells of lupus patients. Arthritis Rheum. 64, 2937–2946 (2012).
Pearce, E. L. et al. Enhancing CD8 T cell memory by modulating fatty acid metabolism. Nature 460, 103–107 (2009).
Michalek, R. D. et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J. Immunol. 186, 3299–3303 (2011).
Spiegel, S. & Milstien, S. Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat. Rev. Mol. Cell. Biol. 4, 397–407 (2003).
Rivera, J., Proia, R. L. & Olivera, A. The alliance of sphingosine-1-phosphate and its receptors in immunity. Nat. Rev. Immunol. 8, 753–763 (2008).
Matloubian, M. et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427, 355–360 (2004).
Liu, G. et al. The receptor S1P1 overrides regulatory T cell-mediated immune suppression through Akt−mTOR. Nat. Immunol. 10, 769–777 (2009).
Liu, G., Yang, K., Burns, S., Shrestha, S. & Chi, H. The S1P1−mTOR axis directs the reciprocal differentiation of TH1 and Treg cells. Nat. Immunol. 11, 1047–1056 (2010).
Hsieh, C. T., Chuang, J. H., Yang, W. C., Yin, Y. & Lin, Y. Ceramide inhibits insulin-stimulated Akt phosphorylation through activation of Rheb/mTORC1/S6K signaling in skeletal muscle. Cell. Signal. 26, 1400–1408 (2014).
Yoshida, S. et al. Redox regulates mammalian target of rapamycin complex 1 (mTORC1) activity by modulating the TSC1/TSC2−Rheb GTPase pathway. J. Biol. Chem. 286, 32651–32660 (2011).
Whitman, M., Downes, C. P., Keeler, M., Keller, T. & Cantley, L. Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate. Nature 332, 644–646 (1988).
Vanhaesebroeck, B., Stephens, L. & Hawkins, P. PI3K signalling: the path to discovery and understanding. Nat. Rev. Mol. Cell. Biol. 13, 195–203 (2012).
Lamming, D. W. et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335, 1638–1643 (2012).
Braccini, L. et al. PI3K-C2γ is a Rab5 effector selectively controlling endosomal Akt2 activation downstream of insulin signalling. Nat. Commun. 6, 7400 (2015).
Kim, J. et al. Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy. Cell 152, 290–303 (2013).
Worby, C. A. & Dixon, J. E. PTEN. Annu. Rev. Biochem. 83, 641–669 (2014).
Sagar, V., Bond, J. R. & Chowdhary, V. R. A 50-year-old woman with Cowden syndrome and joint pains. Arthritis Care Res. 67, 1604–1608 (2015).
Lee, T., Le, E. N., Glass, D. A., Bowen, C. D. & Dominguez, A. R. Systemic lupus erythematosus in a patient with PTEN hamartoma tumour syndrome. Brit. J. Dermatol. 170, 990–992 (2014).
Shrestha, S. et al. Treg cells require the phosphatase PTEN to restrain TH1 and TFH cell responses. Nat. Immunol. 16, 178–187 (2015).
Huynh, A. et al. Control of PI3 kinase in Treg cells maintains homeostasis and lineage stability. Nat. Immunol. 16, 188–196 (2015).
Ray, J. P. & Craft, J. PTENtiating autoimmunity through Treg cell deregulation. Nat. Immunol. 16, 139–140 (2015).
Wu, X. N. et al. Defective PTEN regulation contributes to B cell hyperresponsiveness in systemic lupus erythematosus. Sci. Transl. Med. 6, 246ra99 (2014).
Bluml, S. et al. Loss of phosphatase and tensin homolog (PTEN) in myeloid cells controls inflammatory bone destruction by regulating the osteoclastogenic potential of myeloid cells. Ann. Rheum. Dis. 74, 227–233 (2015).
Inoki, K., Zhu, T. & Guan, K. L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577–590 (2003).
Gwinn, D. M. et al. AMPK phosphorylation of Raptor mediates a metabolic checkpoint. Mol. Cell 30, 214–226 (2008).
Hardie, D. G., Carling, D. & Carlson, M. The AMP-activated/SNF1 protein kinase subfamily: metabolic sensors of the eukaryotic cell? Ann. Rev. Biochem. 67, 821–855 (1998).
Carroll, K. C., Viollet, B. & Suttles, J. AMPKα1 deficiency amplifies proinflammatory myeloid APC activity and CD40 signaling. J. Leukoc. Biol. 94, 1113–1121 (2013).
Russell, R. C. et al. ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nat. Cell Biol. 15, 741–750 (2013).
Kang, K. Y. et al. Metformin downregulates TH17 cells differentiation and attenuates murine autoimmune arthritis. Int. Immunopharmacol. 16, 85–92 (2013).
Araki, K. et al. mTOR regulates memory CD8 T-cell differentiation. Nature 460, 108–112 (2009).
Rao, R. R., Li, Q., Odunsi, K. & Shrikant, P. A. The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet and eomesodermin. Immunity 32, 67–78 (2010).
Delgoffe, G. M. et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30, 832–844 (2009).
Procaccini, C. et al. An oscillatory switch in mTOR kinase activity sets regulatory T cell responsiveness. Immunity 33, 929–941 (2010).
Zeng, H. et al. mTORC1 couples immune signals and metabolic programming to establish Treg-cell function. Nature 499, 485–490 (2013).
Yang, Z., Fujii, H., Mohan, S. V., Goronzy, J. J. & Weyand, C. M. Phosphofructokinase deficiency impairs ATP generation, autophagy, and redox balance in rheumatoid arthritis T cells. J. Exp. Med. 210, 2119–2134 (2013).
Yang, Z., Matteson, E. L., Goronzy, J. J. & Weyand, C. M. T-cell metabolism in autoimmune disease. Arthritis Res. Ther. 17, 29 (2015).
Kato, H. & Perl, A. Mechanistic taret of rapamycin complex 1 expands TH17 and IL-4+ double negative T cells and contracts regulatory T cells in systemic lupus erythematosus. J. Immunol. 192, 4134–4144 (2014).
Fernandez, D. R. & Perl, A. mTOR signaling: a central pathway to pathogenesis in systemic lupus erythematosus? Discov. Med. 9, 173–178 (2010).
Moulton, V. R. & Tsokos, G. C. Abnormalities of T cell signaling in systemic lupus erythematosus. Arth. Res. Ther. 13, 207 (2010).
Lai, Z.-W. et al. mTOR activation triggers IL-4 production and necrotic death of double-negative T cells in patients with systemic lupus eryhthematosus. J. Immunol. 191, 2236–2246 (2013).
Perl, A. mTOR activation is a biomarker and a central pathway to autoimmune disorders, cancer, obesity, and aging. Ann. NY Acad. Sci. 1346, 33–44 (2015).
Tai, T. S., Pai, S. Y. & Ho, I. C. GATA-3 regulates the homeostasis and activation of CD8+ T cells. J. Immunol. 190, 428–437 (2013).
Tomasoni, R. et al. Rapamycin-sensitive signals control TCR/CD28-driven Ifng, Il4 and Foxp3 transcription and promoter region methylation. Eur. J. Immunol. 41, 2086–2096 (2011).
Sieling, P. A. et al. Human double-negative T cells in systemic lupus erythematosus provide help for IgG and are restricted by CD1c. J. Immunol. 165, 5338–5344 (2000).
Shivakumar, S., Tsokos, G. C. & Datta, S. K. T cell receptor α/β expressing double-negative (CD4−/CD8−) and CD4+ T helper cells in humans augment the production of pathogenic anti-DNA autoantibodies associated with lupus nephritis. J. Immunol. 143, 103–112 (1989).
Umekawa, M. & Klionsky, D. J. Ksp1 kinase regulates autophagy via the target of rapamycin complex 1 (TORC1) pathway. J. Biol. Chem. 287, 16300–16310 (2012).
Odegard, J. M. et al. ICOS-dependent extrafollicular helper T cells elicit IgG production via IL-21 in systemic autoimmunity. J. Exp. Med. 205, 2873–2886 (2008).
Le Coz, C. et al. Circulating TFH subset distribution is strongly affected in lupus patients with an active disease. PLoS ONE 8, e75319 (2013).
Singh, N., Birkenbach, M., Caza, T., Perl, A. & Cohen, P. L. Tuberous sclerosis and fulminant lupus in a young woman. J. Clin. Rheumatol. 19, 134–137 (2013).
Wu, T. et al. Shared signaling networks active in B cells isolated from genetically distinct mouse models of lupus. J. Clin. Invest. 117, 2186–2196 (2007).
Stylianou, K. et al. The PI3K/Akt/mTOR pathway is activated in murine lupus nephritis and downregulated by rapamycin. Nephrol. Dial. Transplant. 26, 498–508 (2011).
Tan, E. M. et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 25, 1271–1277 (1982).
Hochberg, M. C. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 40, 1725 (1997).
Petri, M. et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 64, 2677–2686 (2012).
Miyakis, S. et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J. Thromb. Haemost. 4, 295–306 (2006).
Canaud, G. et al. Inhibition of the mTORC pathway in the antiphospholipid syndrome. N. Engl. J. Med. 371, 303–312 (2014).
Lai, Z. W., Marchena-Mendez, I. & Perl, A. Oxidative stress and Treg depletion in lupus patients with anti-phospholipid syndrome. Clin. Immunol. 158, 148–152 (2015).
Doherty, E., Oaks, Z. & Perl, A. Increased mitochondrial electron transport chain activity at complex I is regulated by N-acetylcysteine in lymphocytes of patients with systemic lupus erythematosus. Antiox. Redox Signal. 21, 56–65 (2014).
Yin, Y. et al. Normalization of CD4+ T cell metabolism reverses lupus. Sci. Transl. Med. 7, 274ra18 (2015).
Hanczko, R. et al. Prevention of hepatocarcinogenesis and acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine. J. Clin. Invest. 119, 1546–1557 (2009).
Perl, A., Hanczko, R., Telarico, T., Oaks, Z. & Landas, S. Oxidative stress, inflammation and carcinogenesis are controlled through the pentose phosphate pathway by transaldolase. Trends Mol. Med. 7, 395–403 (2011).
Malemud, C. J. The PI3K/Akt/PTEN/mTOR pathway: a fruitful target for inducing cell death in rheumatoid arthritis? Future Med. Chem. 7, 1137–1147 (2015).
Messaoudi, I., Warner, J. & Nikolich-Zugich, J. Age-related CD8+ T cell clonal expansions express elevated levels of CD122 and CD127 and display defects in perceiving homeostatic signals. J. Immunol. 177, 2784–2792 (2006).
Laragione, T. & Gulko, P. S. mTOR regulates the invasive properties of synovial fibroblasts in rheumatoid arthritis. Mol. Med. 16, 352–358 (2010).
Saxena, A., Raychaudhuri, S. K. & Raychaudhuri, S. P. Interleukin-17-induced proliferation of fibroblast-like synovial cells is mTOR dependent. Arthritis Rheum. 63, 1465–1466 (2011).
Reveille, J. D. Biomarkers for diagnosis, monitoring of progression, and treatment responses in ankylosing spondylitis and axial spondyloarthritis. Clin. Rheumatol. 34, 1009–1018 (2015).
International Genetics of Ankylosing Spondylitis Consortium (IGAS) et al. Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat. Genet. 45, 730–738 (2013).
Robinson, P. C. et al. ERAP2 is associated with ankylosing spondylitis in HLA-B27-positive and HLA-B27-negative patients. Ann. Rheum. Dis. 74, 1627–1629 (2015).
Evans, D. M. et al. Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nat. Genet. 43, 761–767 (2011).
Appel, H. et al. In situ analysis of interleukin-23 and interleukin-12 positive cells in the spine of patients with ankylosing spondylitis. Arthritis Rheum. 65, 1522–1529 (2013).
Lai, N. S. et al. Aberrant expression of microRNAs in T cells from patients with ankylosing spondylitis contributes to the immunopathogenesis. Clin. Exp. Immunol. 173, 47–57 (2013).
Hou, C., Zhu, M., Sun, M. & Lin, Y. MicroRNA let-7i induced autophagy to protect T cell from apoptosis by targeting IGF1R. Biochem. Biophys. Res. Commun. 453, 728–734 (2014).
Kooijman, R., Lauf, J. J., Kappers, A. C. & Rijkers, G. T. Insulin-like growth factor induces phosphorylation of immunoreactive insulin receptor substrate and its association with phosphatidylinositol-3 kinase in human thymocytes. J. Exp. Med. 182, 593–597 (1995).
Kooijman, R., Scholtens, L. E., Rijkers, G. T. & Zegers, B. J. Differential expression of type I insulin-like growth factor receptors in different stages of human T cells. Eur. J. Immunol. 25, 931–935 (1995).
Xu, W. D. et al. Up-regulation of fatty acid oxidation in the ligament as a contributing factor of ankylosing spondylitis: a comparative proteomic study. J. Proteom. 113, 57–72 (2015).
Mease, P. J. Inhibition of interleukin-17, interleukin-23 and the TH17 cell pathway in the treatment of psoriatic arthritis and psoriasis. Curr. Opin. Rheumatol. 27, 127–133 (2015).
Helms, C. et al. A putative RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated with susceptibility to psoriasis. Nat. Genet. 35, 349–356 (2003).
Mitra, A., Raychaudhuri, S. K. & Raychaudhuri, S. P. IL-22 induced cell proliferation is regulated by PI3K/Akt/mTOR signaling cascade. Cytokine 60, 38–42 (2012).
Peled, M. et al. Analysis of programmed death-1 in patients with psoriatic arthritis. Inflammation 38, 1573–1579 (2015).
Javier, A. F. et al. Rapamycin (sirolimus) inhibits proliferating cell nuclear antigen expression and blocks cell cycle in the G1 phase in human keratinocyte stem cells. J. Clin. Invest. 99, 2094–2099 (1997).
Buerger, C., Malisiewicz, B., Eiser, A., Hardt, K. & Boehncke, W. H. Mammalian target of rapamycin and its downstream signalling components are activated in psoriatic skin. Br. J. Dermatol. 169, 156–159 (2013).
Young, C. N. et al. Reactive oxygen species in tumor necrosis factor-α-activated primary human keratinocytes: implications for psoriasis and inflammatory skin disease. J. Invest. Dermatol. 128, 2606–2614 (2008).
Wynn, T. A. Cellular and molecular mechanisms of fibrosis. J. Pathol. 214, 199–210 (2008).
Wilkes, M. C. et al. Transforming growth factor-β activation of phosphatidylinositol 3-kinase is independent of Smad2 and Smad3 and regulates fibroblast responses via p21-activated kinase-2. Cancer Res. 65, 10431–10440 (2005).
Rahimi, R. A. et al. Distinct roles for mammalian target of rapamycin complexes in the fibroblast response to transforming growth factor-β. Cancer Res. 69, 84–93 (2009).
Li, J. et al. Rictor/mTORC2 signaling mediates TGFβ1-induced fibroblast activation and kidney fibrosis. Kidney Int. 88, 515–527 (2015).
Brandt, K. D., Dieppe, P. & Radin, E. Etiopathogenesis of osteoarthritis. Med. Clin. North Am. 93, 1–24 (2009).
Guan, Y., Yang, X., Yang, W., Charbonneau, C. & Chen, Q. Mechanical activation of mammalian target of rapamycin pathway is required for cartilage development. FASEB J. 28, 4470–4481 (2014).
Lotz, M. & Carames, B. Autophagy and cartilage homeostasis mechanisms in joint health, aging and osteoarthritis. Nat. Rev. Rheumatol. 7, 579–587 (2011).
Zhang, Y. et al. Cartilage-specific deletion of mTOR upregulates autophagy and protects mice from osteoarthritis. Ann. Rheum. Dis. 74, 1432–1440 (2015).
Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009).
Sabatini, D. M., Erdjument-Bromage, H., Lui, M., Tempst, P. & Snyder, S. H. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78, 35–43 (1994).
US National Library of Medicine. ClinicalTrials.gov [online].
Chiarini, F., Evangelisti, C., McCubrey, J. A. & Martelli, A. M. Current treatment strategies for inhibiting mTOR in cancer. Trends Pharm. Sci. 36, 124–135 (2015).
Thoreen, C. C. et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J. Biol. Chem. 284, 8023–8032 (2009).
Dancey, J. E. Therapeutic targets: mTOR and related pathways. Cancer Biol. Ther. 5, 1065–1073 (2006).
Peng, L., Zhou, Y., Ye, X. & Zhao, Q. Treatment-related fatigue with everolimus and temsirolimus in patients with cancer meta-analysis of clinical trials. Tumor Biol. 36, 643–654 (2014).
Markman, B. et al. Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors. Ann. Oncol. 23, 2399–2408 (2012).
Aghdasi, B. et al. FKBP12, the 12-kDa FK506-binding protein, is a physiologic regulator of the cell cycle. Proc. Natl Acad. Sci. USA 98, 2425–2430 (2001).
Dolinski, K., Muir, S., Cardenas, M. & Heitman, J. All cyclophilins and FK506 binding proteins are, individually and collectively, dispensable for viability in Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA 94, 13093–13098 (1997).
Houde, V. P. et al. Chronic rapamycin treatment causes glucose intolerance and hyperlipidemia by upregulating hepatic gluconeogenesis and impairing lipid deposition in adipose tissue. Diabetes 59, 1338–1348 (2010).
Fraenkel, M. et al. mTOR inhibition by rapamycin prevents β-cell adaptation to hyperglycemia and exacerbates the metabolic state in type 2 diabetes. Diabetes 57, 945–957 (2008).
Fang, Y. et al. Duration of rapamycin treatment has differential effects on metabolism in mice. Cell. Metab. 17, 456–462 (2013).
Schenone, S., Brullo, C., Musumeci, F., Radi, M. & Botta, M. ATP-competitive inhibitors of mTOR: an update. Curr. Med. Chem. 18, 2995–3014 (2011).
Wang, B. T. et al. The mammalian target of rapamycin regulates cholesterol biosynthetic gene expression and exhibits a rapamycin-resistant transcriptional profile. Proc. Natl Acad. Sci. USA 108, 15201–15206 (2011).
Ramos-Barron, A. et al. Prevention of murine lupus disease in (NZB × NZW)F1 mice by sirolimus treatment. Lupus 16, 775–781 (2007).
Lui, S. L. et al. Rapamycin attenuates the severity of established nephritis in lupus-prone NZB/W F1 mice. Nephrol. Dial. Transplant. 23, 2768–2776 (2008).
Yap, D. Y., Ma, M. K., Tang, C. S. & Chan, T. M. Proliferation signal inhibitors in the treatment of lupus nephritis: preliminary experience. Nephrology (Carlton) 17, 676–680 (2012).
US National Library of Medicine. NCT00779194. ClinicalTrials.gov [online], (2015).
Reitamo, S. et al. Efficacy of sirolimus (rapamycin) administered concomitantly with a subtherapeutic dose of cyclosporin in the treatment of severe psoriasis: a randomized controlled trial. Brit. J. Dermatol. 145, 438–445 (2001).
Niculescu, F. et al. Pathogenic T cells in murine lupus exhibit spontaneous signaling activity through phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways. Arthritis Rheum. 48, 1071–1079 (2003).
Barber, D. F. et al. PI3Kγ inhibition blocks glomerulonephritis and extends lifespan in a mouse model of systemic lupus. Nat. Med. 11, 933–935 (2005).
Suarez-Fueyo, A., Barber, D. F., Martinez-Ara, J., Zea-Mendoza, A. C. & Carrera, A. C. Enhanced phosphoinositide 3-kinase δ activity is a frequent event in systemic lupus erythematosus that confers resistance to activation-induced T cell death. J. Immunol. 187, 2376–2385 (2011).
Suarez-Fueyo, A. et al. Inhibition of PI3Kγ reduces kidney infiltration by macrophages and ameliorates systemic lupus in the mouse. J. Immunol. 193, 544–554 (2014).
Chen, H. et al. Leptin and NAP2 promote mesenchymal stem cell senescence through activation of PI3K/Akt pathway in patients with systemic lupus erythematosus. Arthritis Rheumatol. 67, 2383–2393 (2015).
Bartok, B. et al. PI3 kinase δ is a key regulator of synoviocyte function in rheumatoid arthritis. Am. J. Pathol. 180, 1906–1916 (2012).
Perl, A. Oxidative stress in the pathology and treatment of systemic lupus erythematosus. Nat. Rev. Rheumatol. 9, 674–686 (2013).
Gergely, P. J. et al. Persistent mitochondrial hyperpolarization, increased reactive oxygen intermediate production, and cytoplasmic alkalinization characterize altered IL-10 signaling in patients with systemic lupus erythematosus. J. Immunol. 169, 1092–1101 (2002).
Li, Y., Gorelik, G., Strickland, F. M. & Richardson, B. C. Oxidative stress, T cell DNA methylation and lupus. Arthritis Rheum. 66, 1574–1582 (2014).
Gehrke, N. et al. Oxidative damage of DNA confers resistance to cytosolic nuclease TREX1 degradation and potentiates STING-dependent immune sensing. Immunity 39, 482–495 (2013).
Scofield, R. H. et al. Modification of lupus-associated 60-kDa Ro protein with the lipid oxidation product 4-hydroxy-2-nonenal increases antigenicity and facilitates epitope spreading. Free Radic. Biol. Med. 38, 719–728 (2005).
Otaki, N. et al. Identification of a lipid peroxidation product as the source of oxidation-specific epitopes recognized by anti-DNA autoantibodies. J. Biol. Chem. 285, 33834–33842 (2010).
Gergely, P. J. et al. Mitochondrial hyperpolarization and ATP depletion in patients with systemic lupus erythematosus. Arthritis Rheum. 46, 175–190 (2002).
Shah, D., Aggarwal, A., Bhatnagar, A., Kiran, R. & Wanchu, A. Association between T lymphocyte sub-sets apoptosis and peripheral blood mononuclear cells oxidative stress in systemic lupus erythematosus. Free Radic. Res. 45, 559–567 (2011).
Shah, D., Kiran, R., Wanchu, A. & Bhatnagar, A. Oxidative stress in systemic lupus erythematosus: relationship to TH1 cytokine and disease activity. Immunol. Lett. 129, 7–12 (2010).
Li, K. J. et al. Deranged bioenergetics and defective redox capacity in T lymphocytes and neutrophils are related to cellular dysfunction and increased oxidative stress in patients with active systemic lupus erythematosus. Clin. Dev. Immunol. 2012, 548516 (2012).
Nambiar, M. P. et al. Oxidative stress is involved in the heat stress-induced downregulation of TCRζ chain expression and TCR/CD3-mediated [Ca2+]i response in human T-lymphocytes. Cell. Immunol. 215, 151–161 (2002).
Suwannaroj, S., Lagoo, A., Keisler, D. & McMurray, R. W. Antioxidants suppress mortality in the female NZB × NZW F1 mouse model of systemic lupus erythematosus (SLE). Lupus 10, 258–265 (2001).
Bergamo, P. et al. Conjugated linoleic acid enhances glutathione synthesis and attenuates pathological signs in MRL/MpJ-Faslpr mice. J. Lipid Res. 47, 2382–2391 (2006).
Bergamo, P., Maurano, F. & Rossi, M. Phase 2 enzyme induction by conjugated linoleic acid improves lupus-associated oxidative stress. Free Radic. Biol. Med. 43, 71–79 (2007).
Herzenberg, L. A. et al. Glutathione deficiency is associated with impaired survival in HIV disease. Proc. Natl Acad. Sci. USA 94, 1967–1972 (1997).
Travaline, J. M. et al. Effect of N-acetylcysteine on human diaphragm strength and fatigability. Am. J. Resp. Crit. Care Med. 156, 1567–1571 (1997).
Demedts, M. et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N. Engl. J. Med. 353, 2229–2242 (2005).
Brattstrom, C. et al. Hyperlipidemia in renal transplant recipients treated with sirolimus (rapamycin). Transplantation 65, 1272–1274 (1998).
Qi, W. X., Huang, Y. J., Yao, Y., Shen, Z. & Min, D. L. Incidence and risk of treatment-related mortality with mTOR inhibitors everolimus and temsirolimus in cancer patients: a meta-analysis. PLoS ONE 8, e65166 (2013).
Trager, J. & Ward, M. M. Mortality and causes of death in systemic lupus erythematosus. Curr. Opin. Rheumatol. 13, 345–351 (2001).
Lee, R., Margaritis, M., Channon, K. M. & Antoniades, C. Evaluating oxidative stress in human cardiovascular disease: methodological aspects and considerations. Curr. Med. Chem. 19, 2504–2520 (2012).
Tepel, M., van der Giet, M., Statz, M., Jankowski, J. & Zidek, W. The antioxidant acetylcysteine reduces cardiovascular events in patients with end-stage renal failure. Circulation 107, 992–995 (2003).
Kim, Y. C. & Guan, K. L. mTOR: a pharmacologic target for autophagy regulation. J. Clin. Invest. 125, 25–32 (2015).
Yan, H., Zhou, H. F., Hu, Y. & Pham, C. T. Suppression of experimental arthritis through AMP-activated protein kinase activation and autophagy modulation. J. Rheum. Dis. Treat. 1, 5 (2015).
Martinet, W., De Loof, H. & De Meyer, G. R. mTOR inhibition: a promising strategy for stabilization of atherosclerotic plaques. Atherosclerosis 233, 601–607 (2014).
Balasubramaniam, S. et al. Novel heterozygous mutations in TALDO1 gene causing transaldolase deficiency and early infantile liver failure. J. Pediatr. Gastroenterol. Nutr. 52, 113–116 (2011).
Taniguchi, M. et al. Regulation of autophagy and its associated cell death by 'sphingolipid rheostat': reciprocal role of ceramide and sphingosine 1-phosphate in the mammalian target of rapamycin pathway. J. Biol. Chem. 287, 39898–39910 (2012).
Brinkmann, V. et al. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat. Rev. Drug Discov. 9, 883–897 (2010).
Okazaki, H. et al. Effects of FTY720 in MRL-lpr/lpr mice: therapeutic potential in systemic lupus erythematosus. J. Rheumatol. 29, 707–716 (2002).
Wenderfer, S. E., Stepkowski, S. M. & Braun, M. C. Prolonged survival and reduced renal injury in MRL/lpr mice treated with a novel sphingosine-1-P receptor agonist. Kidney Int. 74, 1319–1326 (2008).
Koga, T. et al. CaMK4-dependent activation of AKT/mTOR and CREM-α underlies autoimmunity-associated TH17 imbalance. J. Clin. Invest. 124, 2234–2245 (2014).
Koga, T. et al. KN-93, an inhibitor of calcium/calmodulin-dependent protein kinase IV, promotes generation and function of Foxp3+ regulatory T cells in MRL/lpr mice. Autoimmunity 47, 445–450 (2014).
Ichinose, K., Juang, Y. T., Crispin, J. C., Kis-Toth, K. & Tsokos, G. C. Inhibition of calcium/calmodulin-dependent protein kinase type IV results in suppression of autoimmunity and organ pathology in lupus-prone mice. Arthritis Rheum. 63, 523–529 (2011).
Fujikawa, K. et al. Calcium/calmodulin-dependent protein kinase II (CaMKII) regulates tumour necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis of fibroblast-like synovial cells (FLS) by phosphorylation of Akt. Clin. Exp. Rheumatol. 27, 952–957 (2009).
Westra, J. et al. Expression and regulation of HIF-1α in macrophages under inflammatory conditions; significant reduction of VEGF by CaMKII inhibitor. BMC Musculoskelet. Disord. 11, 61 (2010).
Yepuri, G. et al. Positive crosstalk between arginase-II and S6K1 in vascular endothelial inflammation and aging. Aging Cell 11, 1005–1016 (2012).
Xiong, Y. et al. ARG2 impairs endothelial autophagy through regulation of MTOR and PRKAA/AMPK signaling in advanced atherosclerosis. Autophagy 10, 2223–2238 (2014).
Elloso, M. M. et al. Protective effect of the immunosuppressant sirolimus against aortic atherosclerosis in apo E-deficient mice. Am. J. Transplant. 3, 562–569 (2003).
Manzi, S. et al. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham study. Am. J. Epidemiol. 145, 408–415 (1997).
Mackey, R. H. et al. Rheumatoid arthritis, anti-CCP positivity, and cardiovascular disease risk in the Women's Health Initiative. Arthritis Rheumatol. 67, 2311–2322 (2015).
Avina-Zubieta, J. A. et al. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Care Res. 59, 1690–1697 (2008).
Soefje, S. A., Karnad, A. & Brenner, A. J. Common toxicities of mammalian target of rapamycin inhibitors. Target. Oncol. 6, 125–129 (2011).
Doran, M. F., Crowson, C. S., Pond, G. R., O'Fallon, W. M. & Gabriel, S. E. Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study. Arthritis Rheum. 46, 2287–2293 (2002).
Paul, M. et al. Methotrexate promotes platelet apoptosis via JNK-mediated mitochondrial damage: alleviation by N-acetylcysteine and N-acetylcysteine amide. PLoS ONE 10, e0127558 (2015).
Laplante, M. & Sabatini, D. M. Regulation of mTORC1 and its impact on gene expression at a glance. J. Cell Sci. 126, 1713–1719 (2013).
Lui, S. L. et al. Rapamycin prevents the development of nephritis in lupus-prone NZB/W F1 mice. Lupus 17, 305–313 (2008).
Kshirsagar, S. et al. Akt-dependent enhanced migratory capacity of TH17 cells from children with lupus nephritis. J. Immunol. 193, 4895–4903 (2014).
Tian, J., Wang, Y., Liu, X., Zhou, X. & Li, R. Rapamycin ameliorates IgA nephropathy via cell cycle-dependent mechanisms. Exp. Biol. Med. (Maywood) 240, 936–945 (2015).
Cruzado, J. M. et al. Low-dose sirolimus combined with angiotensin-converting enzyme inhibitor and statin stabilizes renal function and reduces glomerular proliferation in poor prognosis IgA nephropathy. Nephrol. Dial. Transplant. 26, 3596–3602 (2011).
Zou, Y. et al. Oligodendrocyte precursor cell-intrinsic effect of Rheb1 controls differentiation and mediates mTORC1-dependent myelination in brain. J. Neurosci. 34, 15764–15778 (2014).
Seyfarth, H. J., Hammerschmidt, S., Halank, M., Neuhaus, P. & Wirtz, H. R. Everolimus in patients with severe pulmonary hypertension: a safety and efficacy pilot trial. Pulm. Circ. 3, 632–638 (2013).
Raychaudhuri, S. K. & Raychaudhuri, S. P. mTOR signaling cascade in psoriatic disease: double kinase mTOR inhibitor a novel therapeutic target. Indian J. Dermatol. 59, 67–70 (2014).
Mitra, A. et al. Dual mTOR inhibition is required to prevent TGF-β-mediated fibrosis: implications for scleroderma. J. Invest. Dermatol. 135, 2873–2876 (2015).
Biniecka, M. et al. Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis. Arth. Rheum. 63, 2172–2182 (2011).
Nahir, A. M. et al. Effects of oral N-acetylcysteine on both ocular and oral manifestations of Sjögren's syndrome. 46, 187–192 (1989).
Walters, M. T., Rubin, C. E. & Keightley, S. J. A double-blind, cross-over, study of oral N-acetylcysteine in Sjögren's syndrome. 15, 253–258 (1986).
Kelly, C. & Saravanan, V. Treatment strategies for a rheumatoid arthritis patient with interstitial lung disease. Exp. Opin. Pharmacother. 9, 3221–3230 (2008).
Son, H. J. et al. Metformin attenuates experimental autoimmune arthritis through reciprocal regulation of TH17/Treg balance and osteoclastogenesis. Mediators Inflamm. 2014, 973986 (2014).
Acknowledgements
The author's research work is supported in part by grants AI 048079 and AI 072648 from the National Institutes of Health and the Central New York Community Foundation, and Investigator-Initiated Research Grant P0468X1-4470/WS1234172 from Pfizer.
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Perl, A. Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases. Nat Rev Rheumatol 12, 169–182 (2016). https://doi.org/10.1038/nrrheum.2015.172
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DOI: https://doi.org/10.1038/nrrheum.2015.172
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