Immunometabolism in systemic lupus erythematosus

Nature Reviews Rheumatology

Volumn 13, Issue 5, 2017, Pages 280-290

  Morel, Laurence ^a  

^a UNIVERSITY OF FLORIDA COLLEGE OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE TRIPHOSPHATE; CHEMOKINE RECEPTOR CXCR3; DNA METHYLTRANSFERASE; GAMMA INTERFERON; GLUCOCORTICOID; GLUCOSE TRANSPORTER; GLUTATHIONE; GLYCOSPHINGOLIPID; HISTONE DEACETYLASE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; HYPOXIA INDUCIBLE FACTOR; INTERLEUKIN 17; LIVER X RECEPTOR BETA; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; NITRIC OXIDE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE; T LYMPHOCYTE RECEPTOR; AUTOANTIBODY;

AUTOIMMUNITY; B LYMPHOCYTE; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL DEATH; CELL METABOLISM; CHOLESTEROL METABOLISM; DENDRITIC CELL; DISORDERS OF MITOCHONDRIAL FUNCTIONS; ENZYME ACTIVATION; EPIGENETICS; EXTRACELLULAR TRAP; GENE LOCUS; GENETIC REGULATION; GLUCOSE METABOLISM; HYPOXIA; IMMUNOCOMPETENT CELL; IMMUNOMODULATION; LIPID METABOLISM; LYMPHOCYTE ACTIVATION; LYMPHOCYTE FUNCTION; MACROPHAGE; METABOLIC REGULATION; MICROFLORA; NEUTROPHIL; OXIDATIVE STRESS; PATHOGENESIS; PRIORITY JOURNAL; REVIEW; SYSTEMIC LUPUS ERYTHEMATOSUS; TH1 CELL; TH17 CELL; ANIMAL; DISEASE MODEL; HUMAN; IMMUNOLOGY; METABOLISM; MOUSE;

ANIMALS; AUTOANTIBODIES; B-LYMPHOCYTES; CD4-POSITIVE T-LYMPHOCYTES; DISEASE MODELS, ANIMAL; HUMANS; LUPUS ERYTHEMATOSUS, SYSTEMIC; MICE;

EID: 85016619663     PISSN: 17594790     EISSN: 17594804     Source Type: Journal    
DOI: 10.1038/nrrheum.2017.43     Document Type: Review

References (140)

1. Liu, Z. & Davidson, A. Taming lupus - a new understanding of pathogenesis is leading to clinical advances. Nat. Med. 18, 871-882 (2012).
2. Sang, A., Yin, Y., Zheng, Y.-Y. & Morel, L. in Progress in Molecular Biology and Translational Science Vol. 105 (ed. Conn, P. M.) 321-370 (Academic Press, 2012).
3. Gergely, P. 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).
4. 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).
5. Lai, Z. W. et al. N-Acetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 64, 2937-2946 (2012).
6. Frauwirth, K. A. et al. The CD28 signaling pathway regulates glucose metabolism. Immunity 16, 769-777 (2002).
7. Moulton, V. R. & Tsokos, G. C. T cell signaling abnormalities contribute to aberrant immune cell function and autoimmunity. J. Clin. Invest. 125, 2220-2227 (2015).
8. Fernandez, D. & Perl, A. Metabolic control of T cell activation and death in SLE. Autoimmun. Rev. 8, 184-189 (2009).
9. Choi, S. C., Titov, A. A., Sivakumar, R., Li, W. & Morel, L. Immune metabolism in systemic lupus erythematosus. Curr. Rheumatol. Rep. 18, 66 (2016).
10. Li, W., Sivakumar, R., Titov, A. A., Choi, S. C. & Morel, L. Metabolic factors that contribute to lupus pathogenesis. Crit. Rev. Immunol. 36, 75-98 (2016).
11. Gergely, P. et al. Mitochondrial hyperpolarization and ATP depletion in patients with systemic lupus erythematosus. Arthritis Rheum. 46, 175-190 (2002).
12. Perl, A., Gergely, P. Jr & Banki, K. Mitochondrial dysfunction in T cells of patients with systemic lupus erythematosus. Int. Rev. Immunol. 23, 293-313 (2004).
13. Caza, T. N., Talaber, G. & Perl, A. Metabolic regulation of organelle homeostasis in lupus T cells. Clin. Immunol. 144, 200-213 (2012).
14. Buck, M. D. et al. Mitochondrial dynamics controls T cell fate through metabolic programming. Cell 166, 63-76 (2016).
15. 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. Antioxid. Redox Signal. 21, 56-65 (2014).
16. 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. 17, 395-403 (2011).
17. Perl, A. Oxidative stress in the pathology and treatment of systemic lupus erythematosus. Nat. Rev. Rheumatol. 9, 674-686 (2013).
18. Tsokos, G. C. Systemic lupus erythematosus. N. Engl. J. Med. 365, 2110-2121 (2011).
19. + T cell activation and maps to estrogen-related receptor gamma. J. Immunol. 189, 793-803 (2012).
20. Huss, J. M., Garbacz, W. G. & Xie, W. Constitutive activities of estrogen-related receptors: transcriptional regulation of metabolism by the ERR pathways in health and disease. Biochim. Biophys. Acta 1852, 1912-1927 (2015).
21. Vyshkina, T. et al. Association of common mitochondrial DNA variants with multiple sclerosis and systemic lupus erythematosus. Clin. Immunol. 129, 31-35 (2008).
22. Yu, X. et al. Association of UCP2 -866 G/A polymorphism with chronic inflammatory diseases. Genes Immun. 10, 601-605 (2009).
23. Yang, Z. et al. Restoring oxidant signaling suppresses proarthritogenic T cell effector functions in rheumatoid arthritis. Sci. Transl Med. 8, 331ra38 (2016).
24. Powell, J. D., Pollizzi, K. N., Heikamp, E. B. & Horton, M. R. Regulation of immune responses by mTOR. Annu. Rev. Immunol. 30, 39-68 (2012).
25. Chi, H. Regulation and function of mTOR signalling in T cell fate decisions. Nat. Rev. Immunol. 12, 325-338 (2012).
26. Perl, A. Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases. Nat. Rev. Rheumatol. 12, 169-182 (2016).
27. Zeng, H. et al. mTORC1 couples immune signals and metabolic programming to establish Treg-cell function. Nature 499, 485-490 (2013).
28. Craft, J. E. Follicular helper T cells in immunity and systemic autoimmunity. Nat. Rev. Rheumatol. 8, 337-347 (2012).
29. Blanco, P., Ueno, H. & Schmitt, N. T follicular helper (Tfh) cells in lupus: activation and involvement in SLE pathogenesis. Eur. J. Immunol. 46, 281-290 (2016).
30. Ray, J. P. et al. The interleukin-2-mTORc1 kinase axis defines the signaling, differentiation, and metabolism of T helper 1 and follicular B helper T cells. Immunity 43, 690-702 (2015).
31. Ramiscal, R. R. et al. Attenuation of AMPK signaling by ROQUIN promotes T follicular helper cell formation. eLife 4, e08698 (2015).
32. Pratama, A. et al. MicroRNA-146a regulates ICOS-ICOSL signalling to limit accumulation of T follicular helper cells and germinal centres. Nat. Commun. 6, 6436 (2015).
33. Zeng, H. et al. mTORC1 and mTORC2 kinase signaling and glucose metabolism drive follicular helper t cell differentiation. Immunity 45, 540-554 (2016).
34. Fernandez, D. & Perl, A. mTOR signaling: a central pathway to pathogenesis in systemic lupus erythematosus? Discov. Med. 9, 173-178 (2010).
35. + T cell metabolism reverses lupus. Sci. Transl Med. 7, 274ra18 (2015).
36. + T cell activation in a mouse model of systemic lupus erythematosus. J. Immunol. 196, 80-90 (2016).
37. 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).
38. Lai, Z. W. et al. Mechanistic target of rapamycin activation triggers IL-4 production and necrotic death of double-negative T cells in patients with systemic lupus erythematosus. J. Immunol. 191, 2236-2246 (2013).
39. + CD4-CD8-double-negative T cells and contracts regulatory T cells in systemic lupus erythematosus. J. Immunol. 192, 4134-4144 (2014).
40. Fernandez, D. R. et al. Activation of mammalian target of rapamycin controls the loss of TCRζ in lupus T cells through HRES-1/Rab4-regulated lysosomal degradation. J. Immunol. 182, 2063-2073 (2009).
41. 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).
42. Psarelis, S. & Nikiphorou, E. Coexistence of SLE, tuberous sclerosis and aggressive natural killer-cell leukaemia: coincidence or correlated? Lupus 26, 107-108 (2017).
43. Olde Bekkink, M., Ahmed-Ousenkova, Y. M., Netea, M. G., van der Velden, W. J. & Berden, J. H. Coexistence of systemic lupus erythematosus, tuberous sclerosis and aggressive natural killer-cell leukaemia: coincidence or correlated? Lupus 25, 766-771 (2016).
44. Carrasco Cubero, C., Bejarano Moguel, V., Fernandez Gil, M. A. & Alvarez Vega, J. L. Coincidence of tuberous sclerosis and systemic lupus erythematosus-a case report. Reumatol. Clin. 12, 219-222 (2016).
45. 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).
46. Wahl, D. R. et al. Characterization of the metabolic phenotype of chronically activated lymphocytes. Lupus 19, 1492-1501 (2010).
47. + T cell function under hypoxic conditions. J. Immunol. 196, 106-114 (2016).
48. + T cells to retinoic acid and TGFβ in systemic lupus erythematosus. Arthritis Res. Ther. 13, R106 (2011).
49. Morel, L. et al. Genetic reconstitution of systemic lupus erythematosus immunopathology with polycongenic murine strains. Proc. Natl Acad. Sci. USA 97, 6670-6675 (2000).
50. Macintyre, A. N. et al. The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab. 20, 61-72 (2014).
51. Jacobs, S. R. et al. Glucose uptake is limiting in T cell activation and requires CD28-mediated Akt-dependent and independent pathways. J. Immunol. 180, 4476-4486 (2008).
52. Yang, Z. C. & Liu, Y. Hypoxia-inducible factor-1α and autoimmune lupus, arthritis. Inflammation 39, 1268-1273 (2016).
53. Le Buanec, H. et al. IFN-α and CD46 stimulation are associated with active lupus and skew natural T regulatory cell differentiation to type 1 regulatory T (Tr1) cells. Proc. Natl Acad. Sci. USA 108, 18995-19000 (2011).
54. Kolev, M. et al. Complement regulates nutrient influx and metabolic reprogramming during Th1 cell responses. Immunity 42, 1033-1047 (2015).
55. Kidani, Y. & Bensinger, S. J. Lipids rule: resetting lipid metabolism restores T cell function in systemic lupus erythematosus. J. Clin. Invest. 124, 482-485 (2014).
56. Krishnan, S. et al. Alterations in lipid raft composition and dynamics contribute to abnormal T cell responses in systemic lupus erythematosus. J. Immunol. 172, 7821-7831 (2004).
57. Jury, E. C., Isenberg, D. A., Mauri, C. & Ehrenstein, M. R. Atorvastatin restores Lck expression and lipid raft-associated signaling in T cells from patients with systemic lupus erythematosus. J. Immunol. 177, 7416-7422 (2006).
58. + T cells from lupus patients. J. Clin. Invest. 124, 712-724 (2014).
59. Deng, G. M. & Tsokos, G. C. Cholera toxin B accelerates disease progression in lupus-prone mice by promoting lipid raft aggregation. J. Immunol. 181, 4019-4026 (2008).
60. + T cells by modulating cholesterol metabolism. Nature 531, 651-655 (2016).
61. Wang, F., Beck-Garcia, K., Zorzin, C., Schamel, W. W. A. & Davis, M. M. Inhibition of T cell receptor signaling by cholesterol sulfate, a naturally occurring derivative of membrane cholesterol. Nat. Immunol. 17, 844-850 (2016).
62. Swamy, M. et al. A cholesterol-based allostery model of T cell receptor phosphorylation. Immunity 44, 1091-1101 (2016).
63. Hu, X. et al. Sterol metabolism controls TH17 differentiation by generating endogenous RORγ agonists. Nat. Chem. Biol. 11, 141-147 (2015).
64. Ulivieri, C. & Baldari, C. T. Statins: from cholesterol-lowering drugs to novel immunomodulators for the treatment of Th17-mediated autoimmune diseases. Pharmacol. Res. 88, 41-52 (2014).
65. Waddington, K. E., Jury, E. C. & Pineda-Torra, I. Liver X receptors in immune cell function in humans. Biochem. Soc. Trans. 43, 752-757 (2015).
66. Jeon, J. Y. et al. Liver X receptors alpha gene (NR1H3) promoter polymorphisms are associated with systemic lupus erythematosus in Koreans. Arthritis Res. Ther. 16, R112 (2014).
67. Cui, G. et al. Liver X receptor (LXR) mediates negative regulation of mouse and human Th17 differentiation. J. Clin. Invest. 121, 658-670 (2011).
68. Richard, E. M. et al. Reducing FLI1 levels in the MRL/ lpr lupus mouse model impacts T cell function by modulating glycosphingolipid metabolism. PLoS ONE 8, e75175 (2013).
69. Sundararaj, K. P. et al. FLI1 levels impact CXCR3 expression and renal infiltration of T cells and renal glycosphingolipid metabolism in the MRL/lpr lupus mouse strain. J. Immunol. 195, 5551-5560 (2015).
70. Morris, E. E. et al. A GA microsatellite in the Fli1 promoter modulates gene expression and is associated with systemic lupus erythematosus patients without nephritis. Arthritis Res. Ther. 12, R212 (2010).
71. Nowling, T. K. et al. Renal glycosphingolipid metabolism is dysfunctional in lupus nephritis. J. Am. Soc. Nephrol. 26, 1402-1413 (2015).
72. Murray, P. J., Rathmell, J. & Pearce, E. SnapShot: immunometabolism. Cell Metab. 22, 190-190.e1 (2015).
73. Caro-Maldonado, A. et al. Metabolic reprogramming is required for antibody production that is suppressed in anergic but exaggerated in chronically BAFF-exposed B cells. J. Immunol. 192, 3626-3636 (2014).
74. Aronov, M. & Tirosh, B. Metabolic control of plasma cell differentiation - what we know and what we don't know. J. Clin. Immunol. 36 (Suppl. 1), 12-17 (2016).
75. Benhamron, S., Pattanayak, S. P., Berger, M. & Tirosh, B. mTOR activation promotes plasma cell differentiation and bypasses XBP-1 for immunoglobulin secretion. Mol. Cell. Biol. 35, 153-166 (2015).
76. 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).
77. Zeng, Q. et al. Rapamycin inhibits BAFF-stimulated cell proliferation and survival by suppressing mTOR-mediated PP2A-Erk1/2 signaling pathway in normal and neoplastic B-lymphoid cells. Cell. Mol. Life Sci. 72, 4867-4884 (2015).
78. Lam, W. Y. et al. Mitochondrial pyruvate import promotes long-term survival of antibody-secreting plasma cells. Immunity 45, 60-73 (2016).
79. Pathak, S. et al. Fatty acid amide hydrolase regulates peripheral B cell receptor revision, polyreactivity, and B1 cells in lupus. J. Immunol. 196, 1507-1516 (2016).
80. Lugar, P. L., Love, C., Grammer, A. C., Dave, S. S. & Lipsky, P. E. Molecular characterization of circulating plasma cells in patients with active systemic lupus erythematosus. PLoS ONE 7, e44362 (2012).
81. Aprahamian, T. et al. The peroxisome proliferator-activated receptor γ agonist rosiglitazone ameliorates murine lupus by induction of adiponectin. J. Immunol. 182, 340-346 (2009).
82. Aprahamian, T. R., Bonegio, R. G., Weitzner, Z., Gharakhanian, R. & Rifkin, I. R. Peroxisome proliferator-activated receptor gamma agonists in the prevention and treatment of murine systemic lupus erythematosus. Immunology 142, 363-373 (2014).
83. Venegas-Pont, M. et al. Rosiglitazone decreases blood pressure and renal injury in a female mouse model of systemic lupus erythematosus. Am. J. Physiol. Regul. Integr. Comp. Physiol. 296, R1282-R1289 (2009).
84. Zhao, W. et al. The peroxisome proliferator-activated receptor gamma agonist pioglitazone improves cardiometabolic risk and renal inflammation in murine lupus. J. Immunol. 183, 2729-2740 (2009).
85. O'Neill, L. A. & Pearce, E. J. Immunometabolism governs dendritic cell and macrophage function. J. Exp. Med. 213, 15-23 (2016).
86. Ravishankar, B. et al. Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase. Proc. Natl Acad. Sci. USA 109, 3909-3914 (2012).
87. Ravishankar, B. et al. The amino acid sensor GCN2 inhibits inflammatory responses to apoptotic cells promoting tolerance and suppressing systemic autoimmunity. Proc. Natl Acad. Sci. USA 112, 10774-10779 (2015).
88. Tsalikis, J., Croitoru, D. O., Philpott, D. J. & Girardin, S. E. Nutrient sensing and metabolic stress pathways in innate immunity. Cell. Microbiol. 15, 1632-1641 (2013).
89. McGaha, T. L. IDO-GCN2 and autophagy in inflammation. Oncotarget 6, 21771-21772 (2015).
90. + T-cells. Int. J. Mol. Med. 37, 1412-1420 (2016).
91. Sukhbaatar, N., Hengstschlager, M. & Weichhart, T. mTOR-mediated regulation of dendritic cell differentiation and function. Trends Immunol. 37, 778-789 (2016).
92. 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).
93. Wu, D. et al. Type 1 interferons induce changes in core metabolism that are critical for immune function. Immunity 44, 1325-1336 (2016).
94. Berod, L. et al. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat. Med. 20, 1327-1333 (2014).
95. Smith, C. K. & Kaplan, M. J. The role of neutrophils in the pathogenesis of systemic lupus erythematosus. Curr. Opin. Rheumatol. 27, 448-453 (2015).
96. Lood, C. et al. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat. Med. 22, 146-153 (2016).
97. Caielli, S. et al. Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus. J. Exp. Med. 213, 697-713 (2016).
98. Campbell, A. M., Kashgarian, M. & Shlomchik, M. J. NADPH oxidase inhibits the pathogenesis of systemic lupus erythematosus. Sci. Transl Med. 4, 157ra141 (2012).
99. Bao, Y. et al. mTOR and differential activation of mitochondria orchestrate neutrophil chemotaxis. J. Cell Biol. 210, 1153-1164 (2015).
100. Oaks, Z. & Perl, A. Metabolic control of the epigenome in systemic lupus erythematosus. Autoimmunity 47, 256-264 (2014).
101. Richardson, B. C. & Patel, D. R. Epigenetics in 2013: DNA methylation and miRNA - key roles in systemic autoimmunity. Nat. Rev. Rheumatol. 10, 72-74 (2014).
102. Wu, T. et al. Metabolic disturbances associated with systemic lupus erythematosus. PLoS ONE 7, e37210 (2012).
103. + T cells favoring T cell activation and non-Th1 effector T cell immune response as an early event in lupus flares. Arthritis Rheumatol. 68, 2200-2209 (2016).
104. Zhao, E. et al. Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction. Nat. Immunol. 17, 95-103 (2016).
105. Regna, N. L. et al. HDAC expression and activity is upregulated in diseased lupus-prone mice. Int. Immunopharmacol. 29, 494-503 (2015).
106. Mishra, N., Reilly, C. M., Brown, D. R., Ruiz, P. & Gilkeson, G. S. Histone deacetylase inhibitors modulate renal disease in the MRL-lpr/lpr mouse. J. Clin. Invest. 111, 539-552 (2003).
107. Long, H., Yin, H., Wang, L., Gershwin, M. E. & Lu, Q. The critical role of epigenetics in systemic lupus erythematosus and autoimmunity. J. Autoimmun. 74, 118-138 (2016).
108. Corcoran, S. E. & O'Neill, L. A. HIF1α and metabolic reprogramming in inflammation. J. Clin. Invest. 126, 3699-3707 (2016).
109. Shi, L. Z. et al. HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J. Exp. Med. 208, 1367-1376 (2011).
110. Kohler, T., Reizis, B., Johnson, R. S., Weighardt, H. & Forster, I. Influence of hypoxia-inducible factor 1α on dendritic cell differentiation and migration. Eur. J. Immunol. 42, 1226-1236 (2012).
111. Cho, S. H. et al. Germinal centre hypoxia and regulation of antibody qualities by a hypoxia response system. Nature 537, 234-238 (2016).
112. Feng, C. C. et al. Lack of association between the polymorphisms of hypoxia-inducible factor 1A (HIF1A) gene and SLE susceptibility in a Chinese population. Immunogenetics 66, 9-13 (2014).
113. Davidson, A. What is damaging the kidney in lupus nephritis? Nat. Rev. Rheumatol. 12, 143-153 (2016).
114. Bethunaickan, R. et al. Identification of stage-specific genes associated with lupus nephritis and response to remission induction in (NZB x NZW)F1 and NZM2410 mice. Arthritis Rheumatol. 66, 2246-2258 (2014).
115. Mashmoushi, A. K. & Oates, J. C. Lipopolysaccharide induces inducible nitric oxide synthase-dependent podocyte dysfunction via a hypoxia-inducible factor 1α and cell division control protein 42 and Ras-related C3 botulinum toxin substrate 1 pathway. Free Radic. Biol. Med. 84, 185-195 (2015).
116. Deng, W. et al. Hypoxia inducible factor-1 alpha promotes mesangial cell proliferation in lupus nephritis. Am. J. Nephrol. 40, 507-515 (2014).
117. Bengtsson, A. A. et al. Metabolic profiling of systemic lupus erythematosus and comparison with primary Sjögren's syndrome and systemic sclerosis. PLoS ONE 11, e0159384 (2016).
118. Lood, C. et al. Type I interferon-mediated skewing of the serotonin synthesis is associated with severe disease in systemic lupus erythematosus. PLoS ONE 10, e0125109 (2015).
119. Pedersen, H. K. et al. Human gut microbes impact host serum metabolome and insulin sensitivity. Nature 535, 376-381 (2016).
120. Hevia, A. et al. Intestinal dysbiosis associated with systemic lupus erythematosus. mBio 5, e01548-14 (2014).
121. Lopez, P. et al. Th17 responses and natural IgM antibodies are related to gut microbiota composition in systemic lupus erythematosus patients. Sci. Rep. 6, 24072 (2016).
122. Rojo, D. et al. Ranking the impact of human health disorders on gut metabolism: systemic lupus erythematosus and obesity as study cases. Sci. Rep. 5, 8310 (2015).
123. Serrano-Villar, S. et al. HIV infection results in metabolic alterations in the gut microbiota different from those induced by other diseases. Sci. Rep. 6, 26192 (2016).
124. Keller, K. E., Tan, I. S. & Lee, Y. S. SAICAR stimulates pyruvate kinase isoform M2 and promotes cancer cell survival in glucose-limited conditions. Science 338, 1069-1072 (2012).
125. Mills, E. & O'Neill, L. A. Succinate: a metabolic signal in inflammation. Trends Cell Biol. 24, 313-320 (2014).
126. Correa-Oliveira, R., Fachi, J. L., Vieira, A., Sato, F. T. & Vinolo, M. A. Regulation of immune cell function by short-chain fatty acids. Clin. Transl Immunology 5, e73 (2016).
127. Pasquier, B. Autophagy inhibitors. Cell. Mol. Life Sci. 73, 985-1001 (2016).
128. Domhan, S. et al. Molecular mechanisms of the antiangiogenic and antitumor effects of mycophenolic acid. Mol. Cancer Ther. 7, 1656-1668 (2008).
129. Dun, B. Y. et al. Transcriptomic changes induced by mycophenolic acid in gastric cancer cells. Am. J. Transl Res. 6, 28-42 (2014).
130. + T cells: more than mere guanine nucleotide deprivation. Am. J. Transplant. 11, 439-449 (2011).
131. 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).
132. Rhoads, J. P., Major, A. S. & Rathmell, J. C. Fine tuning of immune metabolism for the treatment of rheumatic diseases. Nat. Rev. Rheumatol. (in press).
133. Fernández-Ramos, A. A., Poindessous, V., Marchetti-Laurent, C., Pallet, N. & Loriot, M.-A. The effect of immunosuppressive molecules on T-cell metabolic reprogramming. Biochimie 127, 23-36 (2016).
134. Tanaka, N., Kusunoki, N., Kusunoki, Y., Hasunuma, T. & Kawai, S. Resistin is associated with the inflammation process in patients with systemic autoimmune diseases undergoing glucocorticoid therapy: comparison with leptin and adiponectin. Mod. Rheumatol. 23, 8-18 (2013).
135. Tanaka, N., Masuoka, S., Kusunoki, N., Nanki, T. & Kawai, S. Serum resistin level and progression of atherosclerosis during glucocorticoid therapy for systemic autoimmune diseases. Metabolites 6, E28 (2016).
136. Mejia, P. et al. Dietary restriction protects against experimental cerebral malaria via leptin modulation and T-cell mTORC1 suppression. Nat. Commun. 6, 6050 (2015).
137. Zhao, W. et al. The peroxisome-proliferator activated receptor-γ agonist pioglitazone modulates aberrant T cell responses in systemic lupus erythematosus. Clin. Immunol. 149, 119-132 (2013).
138. Bride, K. L. et al. Sirolimus is effective in relapsed/ refractory autoimmune cytopenias: results of a prospective multi-institutional trial. Blood 127, 17-28 (2016).
139. Oaks, Z., Winans, T., Huang, N., Banki, K. & Perl, A. Activation of the mechanistic target of rapamycin in SLE: explosion of evidence in the last five years. Curr. Rheumatol. Rep. 18, 73 (2016).
140. 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).