Skip to main content

Advertisement

SpringerLink
Log in

Leptin: an unappreciated key player in SLE

  • Review Article
  • Published:
Clinical Rheumatology Aims and scope Submit manuscript

Abstract

Leptin is the forerunner of the adipokine superfamily and plays a key role in regulating energy expenditure and neuroendocrine function. Researches into leptin put emphasize not only on the metabolic role but also its immunoregulatory effect on immune response through immunocyte activation and cytokine secretion. Leptin acts on receptors that are widespread throughout the body and that are expressed across many tissue types. As a consequence, the abnormal expression of leptin has been found to correlate with a number of diseases, including cancers, autoimmune diseases, and cardiovascular diseases. The significance of leptin in the development of autoimmune diseases is becoming increasingly prominent. Systemic lupus erythematosus (SLE) is a severe atypical autoimmune disease that causes damage to multiple organ systems. It is characterised by the following: impaired clearance of apoptotic cells, loss of tolerance to self-antigens, aberrant activation of T cells and B cells, and chronic inflammation. The heightened immunocyte response in SLE means that these physiological systems are particularly vulnerable to regulation by leptin in addition to being of great significance to the research field. Our current review provides insight into the regulatory roles that leptin plays on immune effector cells in SLE.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Zabeau L, Wauman J, Dam J, Van Lint S, Burg E, De Geest J, Rogge E, Silva A, Jockers R, Tavernier J (2019) A novel leptin receptor antagonist uncouples leptin’s metabolic and immune functions. Cell Mol Life Sci 76(6):1201–1214. https://doi.org/10.1007/s00018-019-03004-9

    Article  CAS  PubMed  Google Scholar 

  2. Navarini L, Margiotta DPE, Vadacca M, Afeltra A (2018) Leptin in autoimmune mechanisms of systemic rheumatic diseases. Cancer Lett 423:139–146. https://doi.org/10.1016/j.canlet.2018.03.011

    Article  CAS  PubMed  Google Scholar 

  3. Matarese G, Carrieri PB, La Cava A, Perna F, Sanna V, De Rosa V, Aufiero D, Fontana S, Zappacosta S (2005) Leptin increase in multiple sclerosis associates with reduced number of CD4(+)CD25(+) regulatory T cells. P Natl Acad Sci USA 102(14):5150–5155. https://doi.org/10.1073/pnas.0408995102

    Article  CAS  Google Scholar 

  4. Sari I, Demir T, Kozaci LD, Akar S, Kavak T, Birlik M, Onen F, Akkoc N (2007) Body composition, insulin, and leptin levels in patients with ankylosing spondylitis. Clin Rheumatol 26(9):1427–1432. https://doi.org/10.1007/s10067-006-0509-6

    Article  PubMed  Google Scholar 

  5. Choi MY, Flood K, Bernatsky S, Ramsey-Goldman R, Clarke AE (2017) A review on SLE and malignancy. Best Pract Res Clin Rheumatol 31(3):373–396. https://doi.org/10.1016/j.berh.2017.09.013

    Article  PubMed  PubMed Central  Google Scholar 

  6. Mohamed A, Chen Y, Wu H, Liao J, Cheng B, Lu Q (2019) Therapeutic advances in the treatment of SLE. Int Immunopharmacol 72:218–223. https://doi.org/10.1016/j.intimp.2019.03.010

    Article  CAS  PubMed  Google Scholar 

  7. Xu WD, Zhang M, Zhang YJ, Liu SS, Pan HF, Ye DQ (2014) Association between leptin and systemic lupus erythematosus. Rheumatol Int 34(4):559–563. https://doi.org/10.1007/s00296-013-2774-4

    Article  CAS  PubMed  Google Scholar 

  8. Dammacco R (2018) Systemic lupus erythematosus and ocular involvement: an overview. Clin Exp Med 18(2):135–149. https://doi.org/10.1007/s10238-017-0479-9

    Article  CAS  PubMed  Google Scholar 

  9. Pisetsky DS (2008) The role of innate immunity in the induction of autoimmunity. Autoimmun Rev 8(1):69–72. https://doi.org/10.1016/j.autrev.2008.07.028

    Article  CAS  PubMed  Google Scholar 

  10. Weidenbusch M, Kulkarni OP, Anders HJ (2017) The innate immune system in human systemic lupus erythematosus. Clinical science (London, England: 1979) 131(8):625–634. https://doi.org/10.1042/cs20160415

    Article  CAS  Google Scholar 

  11. Teh P, Zakhary B, Sandhu VK (2019) The impact of obesity on SLE disease activity: findings from the Southern California Lupus Registry (SCOLR). Clin Rheumatol 38(2):597–600. https://doi.org/10.1007/s10067-018-4336-3

    Article  PubMed  Google Scholar 

  12. Diaz-Rizo V, Bonilla-Lara D, Gonzalez-Lopez L, Sanchez-Mosco D, Fajardo-Robledo NS, Perez-Guerrero EE, Rodriguez-Jimenez NA, Saldana-Cruz AM, Vazquez-Villegas ML, Gomez-Banuelos E, Vazquez-Del Mercado M, Cardona-Munoz EG, Cardona-Muller D, Trujillo X, Huerta M, Salazar-Paramo M, Gamez-Nava JI (2017) Serum levels of adiponectin and leptin as biomarkers of proteinuria in lupus nephritis. PLoS One 12(9):e0184056. https://doi.org/10.1371/journal.pone.0184056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Barranco C (2016) Systemic lupus erythematosus: leptin linked to SLE. Nat Rev Rheumatol 12(11):623. https://doi.org/10.1038/nrrheum.2016.161

    Article  PubMed  Google Scholar 

  14. Lourenco EV, Liu A, Matarese G, La Cava A (2016) Leptin promotes systemic lupus erythematosus by increasing autoantibody production and inhibiting immune regulation. Proc Natl Acad Sci U S A 113(38):10637–10642. https://doi.org/10.1073/pnas.1607101113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Mohammed SF, Abdalla MA, Ismaeil WM, Sheta MM (2018) Serum leptin in systemic lupus erythematosus patients: its correlation with disease activity and some disease parameters. The Egyptian Rheumatologist 40(1):23–27. https://doi.org/10.1016/j.ejr.2017.06.005

    Article  Google Scholar 

  16. Abella V, Scotece M, Conde J, Pino J, Gonzalez-Gay MA, Gomez-Reino JJ, Mera A, Lago F, Gomez R, Gualillo O (2017) Leptin in the interplay of inflammation, metabolism and immune system disorders. Nat Rev Rheumatol 13(2):100–109. https://doi.org/10.1038/nrrheum.2016.209

    Article  CAS  PubMed  Google Scholar 

  17. La Cava A (2017) Leptin in inflammation and autoimmunity. Cytokine 98:51–58. https://doi.org/10.1016/j.cyto.2016.10.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Procaccini C, La Rocca C, Carbone F, De Rosa V, Galgani M, Matarese G (2017) Leptin as immune mediator: interaction between neuroendocrine and immune system. Dev Comp Immunol 66:120–129. https://doi.org/10.1016/j.dci.2016.06.006

    Article  CAS  PubMed  Google Scholar 

  19. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372(6505):425–432. https://doi.org/10.1038/372425a0

    Article  CAS  PubMed  Google Scholar 

  20. Munzberg H, Morrison CD (2015) Structure, production and signaling of leptin. Metabolism 64(1):13–23. https://doi.org/10.1016/j.metabol.2014.09.010

    Article  CAS  PubMed  Google Scholar 

  21. Perez-Perez A, Vilarino-Garcia T, Fernandez-Riejos P, Martin-Gonzalez J, Segura-Egea JJ, Sanchez-Margalet V (2017) Role of leptin as a link between metabolism and the immune system. Cytokine Growth Factor Rev 35:71–84. https://doi.org/10.1016/j.cytogfr.2017.03.001

    Article  CAS  PubMed  Google Scholar 

  22. Wasim M, Awan FR, Najam SS, Khan AR, Khan HN (2016) Role of leptin deficiency, inefficiency, and leptin receptors in obesity. Biochem Genet 54(5):565–572. https://doi.org/10.1007/s10528-016-9751-z

    Article  CAS  PubMed  Google Scholar 

  23. Akther A, Khan KH, Begum M, Parveen S, Kaiser MS, Chowdhury AZ (2009) Leptin: a mysterious hormone; its physiology and pathophysiology. Mymensingh Med J 18(1 Suppl):S140–S144

    PubMed  Google Scholar 

  24. Crujeiras AB, Carreira MC, Cabia B, Andrade S, Amil M, Casanueva FF (2015) Leptin resistance in obesity: an epigenetic landscape. Life Sci 140:57–63. https://doi.org/10.1016/j.lfs.2015.05.003

    Article  CAS  PubMed  Google Scholar 

  25. Gulkesen A, Akgol G, Tuncer T, Kal GA, Telo S, Poyraz AK, Kaya A (2016) Relationship between leptin and neopterin levels and disease activation parameters in patients with rheumatoid arthritis. Arch Rheumatol 31(4):333–339. https://doi.org/10.5606/ArchRheumatol.2016.5893

    Article  PubMed  PubMed Central  Google Scholar 

  26. Jenks MZ, Fairfield HE, Johnson EC, Morrison RF, Muday GK (2017) Sex steroid hormones regulate leptin transcript accumulation and protein secretion in 3T3-L1 cells. Sci Rep 7(1):8232. https://doi.org/10.1038/s41598-017-07473-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. MacIver NJ, Thomas SM, Green CL, Worley G (2016) Increased leptin levels correlate with thyroid autoantibodies in nonobese males. Clin Endocrinol 85(1):116–121. https://doi.org/10.1111/cen.12963

    Article  CAS  Google Scholar 

  28. Li HM, Zhang TP, Leng RX, Li XP, Wang DG, Li XM, Ye DQ, Pan HF (2017) Association of leptin and leptin receptor gene polymorphisms with systemic lupus erythematosus in a Chinese population. J Cell Mol Med 21(9):1732–1741. https://doi.org/10.1111/jcmm.13093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Myers MG, Cowley MA, Munzberg H (2008) Mechanisms of leptin action and leptin resistance. Annu Rev Physiol 70:537–556. https://doi.org/10.1146/annurev.physiol.70.113006.100707

    Article  CAS  PubMed  Google Scholar 

  30. Tsiotra PC, Boutati E, Dimitriadis G, Raptis SA (2013) High insulin and leptin increase resistin and inflammatory cytokine production from human mononuclear cells. Biomed Res Int 2013:487081. https://doi.org/10.1155/2013/487081

    Article  CAS  PubMed  Google Scholar 

  31. Jog N, Caricchio R, Cohen P (2014) The neutrophil: an underappreciated but key player in SLE pathogenesis. Curr Immunol Rev 9(4):222–230. https://doi.org/10.2174/1573395510666140301005421

    Article  CAS  Google Scholar 

  32. Li SF, Li X (2016) Leptin in normal physiology and leptin resistance. Sci Bull 61(19):1480–1488. https://doi.org/10.1007/s11434-015-0951-4

    Article  CAS  Google Scholar 

  33. Wada N, Hirako S, Takenoya F, Kageyama H, Okabe M, Shioda S (2014) Leptin and its receptors. J Chem Neuroanat 61–62:191–199. https://doi.org/10.1016/j.jchemneu.2014.09.002

    Article  CAS  PubMed  Google Scholar 

  34. Schaab M, Kratzsch J (2015) The soluble leptin receptor. Best Pract Res Clin Endocrinol Metab 29(5):661–670. https://doi.org/10.1016/j.beem.2015.08.002

    Article  CAS  PubMed  Google Scholar 

  35. Uddin S, Mohammad RM (2016) Role of leptin and leptin receptors in hematological malignancies. Leuk Lymphoma 57(1):10–16. https://doi.org/10.3109/10428194.2015.1063145

    Article  CAS  PubMed  Google Scholar 

  36. Mullen M, Gonzalez-Perez RR (2016) Leptin-induced JAK/STAT signaling and cancer growth. Vaccines (Basel) 4(3). https://doi.org/10.3390/vaccines4030026

    Article  PubMed Central  Google Scholar 

  37. Park HK, Ahima RS (2014) Leptin signaling. F1000Prime Rep 6:73. https://doi.org/10.12703/P6-73

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Gavello D, Carbone E, Carabelli V (2016) Leptin-mediated ion channel regulation: PI3K pathways, physiological role, and therapeutic potential. Channels 10(4):282–296. https://doi.org/10.1080/19336950.2016.1164373

    Article  PubMed  PubMed Central  Google Scholar 

  39. Li F, Yang Y, Zhu X, Huang L, Xu J (2015) Macrophage polarization modulates development of systemic lupus erythematosus. Cell Physiol Biochem 37(4):1279–1288. https://doi.org/10.1159/000430251

    Article  CAS  PubMed  Google Scholar 

  40. Benso L (2016) Differential function of in vitro generated macrophages from systemic lupus erythematosus and non-diseased peripheral blood mononuclear cells. Harveard Extension School Master’s thesis

  41. Ren Y, Tang J, Mok MY, Chan AW, Wu A, Lau CS (2003) Increased apoptotic neutrophils and macrophages and impaired macrophage phagocytic clearance of apoptotic neutrophils in systemic lupus erythematosus. Arthritis Rheum 48(10):2888–2897. https://doi.org/10.1002/art.11237

    Article  PubMed  Google Scholar 

  42. Munoz LE, Lauber K, Schiller M, Manfredi AA, Schett G, Voll RE, Herrmann M (2010) The role of incomplete clearance of apoptotic cells in the etiology and pathogenesis of SLE. Z Rheumatol 69(2):152, 154–152, 156. https://doi.org/10.1007/s00393-009-0603-7

    Article  Google Scholar 

  43. Mahajan A, Herrmann M, Munoz LE (2016) Clearance deficiency and cell death pathways: a model for the pathogenesis of SLE. Front Immunol 7:35. https://doi.org/10.3389/fimmu.2016.00035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. de Zubiria SA, Herrera-Diaz C (2012) Lupus nephritis: an overview of recent findings. Autoimmune Dis 2012:849684. https://doi.org/10.1155/2012/849684

    Article  CAS  Google Scholar 

  45. Byrne JC, Ni Gabhann J, Lazzari E, Mahony R, Smith S, Stacey K, Wynne C, Jefferies CA (2012) Genetics of SLE: functional relevance for monocytes/macrophages in disease. Clin Dev Immunol 2012:582352. https://doi.org/10.1155/2012/582352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Katsiari CG, Liossis SN, Sfikakis PP (2010) The pathophysiologic role of monocytes and macrophages in systemic lupus erythematosus: a reappraisal. Semin Arthritis Rheum 39(6):491–503. https://doi.org/10.1016/j.semarthrit.2008.11.002

    Article  CAS  PubMed  Google Scholar 

  47. Su DL, Lu ZM, Shen MN, Li X, Sun LY (2012) Roles of pro- and anti-inflammatory cytokines in the pathogenesis of SLE. J Biomed Biotechnol 2012:347141. https://doi.org/10.1155/2012/347141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Macauley MS, Crocker PR, Paulson JC (2014) Siglec-mediated regulation of immune cell function in disease. Nat Rev Immunol 14(10):653–666. https://doi.org/10.1038/nri3737

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Acedo SC, Gambero S, Cunha FG, Lorand-Metze I, Gambero A (2013) Participation of leptin in the determination of the macrophage phenotype: an additional role in adipocyte and macrophage crosstalk. In Vitro Cell Dev Biol Anim 49(6):473–478. https://doi.org/10.1007/s11626-013-9629-x

    Article  CAS  PubMed  Google Scholar 

  50. Conde J, Scotece M, Abella V, Lopez V, Pino J, Gomez-Reino JJ, Gualillo O (2014) An update on leptin as immunomodulator. Expert Rev Clin Immunol 10(9):1165–1170. https://doi.org/10.1586/1744666X.2014.942289

    Article  CAS  PubMed  Google Scholar 

  51. Liu L, Allman WR, Coleman AS, Takeda K, Lin TL, Akkoyunlu M (2018) Delayed onset of autoreactive antibody production and M2-skewed macrophages contribute to improved survival of TACI deficient MRL-Fas/Lpr mouse. Sci Rep 8(1):1308. https://doi.org/10.1038/s41598-018-19827-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Amarilyo G, Iikuni N, Liu A, Matarese G, La Cava A (2014) Leptin enhances availability of apoptotic cell-derived self-antigen in systemic lupus erythematosus. PLoS One 9(11):e112826. https://doi.org/10.1371/journal.pone.0112826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Jiang JX, Mikami K, Shah VH, Torok NJ (2008) Leptin induces phagocytosis of apoptotic bodies by hepatic stellate cells via a Rho guanosine triphosphatase-dependent mechanism. Hepatology 48(5):1497–1505. https://doi.org/10.1002/hep.22515

    Article  CAS  PubMed  Google Scholar 

  54. Jaedicke KM, Roythorne A, Padget K, Todryk S, Preshaw PM, Taylor JJ (2013) Leptin up-regulates TLR2 in human monocytes. J Leukoc Biol 93(4):561–571. https://doi.org/10.1189/jlb.1211606

    Article  CAS  PubMed  Google Scholar 

  55. Liu F, Li X, Yue H, Ji J, You M, Ding L, Fan H, Hou Y (2017) TLR-induced SMPD3 defects enhance inflammatory response of B cell and macrophage in the pathogenesis of SLE. Scand J Immunol 86(5):377–388. https://doi.org/10.1111/sji.12611

    Article  CAS  PubMed  Google Scholar 

  56. Murata T, Asanuma K, Ara N, Iijima K, Hatta W, Hamada S, Asano N, Koike T, Imatani A, Masamune A, Shimosegawa T (2018) Leptin aggravates reflux esophagitis by increasing tissue levels of macrophage migration inhibitory factor in rats. Tohoku J Exp Med 245(1):45–53. https://doi.org/10.1620/tjem.245.45

    Article  CAS  PubMed  Google Scholar 

  57. Zarkesh-Esfahani H, Pockley G, Metcalfe RA, Bidlingmaier M, Wu Z, Ajami A, Weetman AP, Strasburger CJ, Ross RJ (2001) High-dose leptin activates human leukocytes via receptor expression on monocytes. J Immunol 167(8):4593–4599

    Article  CAS  PubMed  Google Scholar 

  58. Naylor C, Petri WA Jr (2016) Leptin regulation of immune responses. Trends Mol Med 22(2):88–98. https://doi.org/10.1016/j.molmed.2015.12.001

    Article  CAS  PubMed  Google Scholar 

  59. Gabay C, Dreyer M, Pellegrinelli N, Chicheportiche R, Meier CA (2001) Leptin directly induces the secretion of interleukin 1 receptor antagonist in human monocytes. J Clin Endocrinol Metab 86(2):783–791. https://doi.org/10.1210/jcem.86.2.7245

    Article  CAS  PubMed  Google Scholar 

  60. Vaughan T, Li L (2010) Molecular mechanism underlying the inflammatory complication of leptin in macrophages. Mol Immunol 47(15):2515–2518. https://doi.org/10.1016/j.molimm.2010.06.006

    Article  CAS  PubMed  Google Scholar 

  61. Yang ZX, Zhang ZY, Lin F, Ren YP, Liu DH, Zhong RQ, Liang Y (2017) Comparisons of neutrophil-, monocyte-, eosinophil-, and basophil- lymphocyte ratios among various systemic autoimmune rheumatic diseases. Apmis 125(10):863–871. https://doi.org/10.1111/apm.12722

    Article  CAS  PubMed  Google Scholar 

  62. Bennett L, Palucka AK, Arce E, Cantrell V, Borvak J, Banchereau J, Pascual V (2003) Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med 197(6):711–723. https://doi.org/10.1084/jem.20021553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Bekeredjian-Ding IB, Wagner M, Hornung V, Giese T, Schnurr M, Endres S, Hartmann G (2005) Plasmacytoid dendritic cells control TLR7 sensitivity of naive B cells via type I IFN. J Immunol 174(7):4043–4050

    Article  PubMed  Google Scholar 

  64. Green NM, Laws A, Kiefer K, Busconi L, Kim YM, Brinkmann MM, Trail EH, Yasuda K, Christensen SR, Shlomchik MJ, Vogel S, Connor JH, Ploegh H, Eilat D, Rifkin IR, van Seventer JM, Marshak-Rothstein A (2009) Murine B cell response to TLR7 ligands depends on an IFN-beta feedback loop. J Immunol 183(3):1569–1576. https://doi.org/10.4049/jimmunol.0803899

    Article  CAS  PubMed  Google Scholar 

  65. Han JH, Umiker BR, Kazimirova AA, Fray M, Korgaonkar P, Selsing E, Imanishi-Kari T (2014) Expression of an anti-RNA autoantibody in a mouse model of SLE increases neutrophil and monocyte numbers as well as IFN-I expression. Eur J Immunol 44(1):215–226. https://doi.org/10.1002/eji.201343714

    Article  CAS  PubMed  Google Scholar 

  66. Courtney PA, Crockard AD, Williamson K, Irvine AE, Kennedy RJ, Bell AL (1999) Increased apoptotic peripheral blood neutrophils in systemic lupus erythematosus: relations with disease activity, antibodies to double stranded DNA, and neutropenia. Ann Rheum Dis 58(5):309–314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Guo X, Fang X, He G, Zaman MH, Fei X, Qiao W, Deng GM (2018) The role of neutrophils in skin damage induced by tissue-deposited lupus IgG. Immunology. https://doi.org/10.1111/imm.12908

    Article  CAS  PubMed Central  Google Scholar 

  68. van Dam LS, Rabelink TJ, van Kooten C, Teng YKO (2019) Clinical implications of excessive neutrophil extracellular trap formation in renal autoimmune diseases. Kidney Int Rep 4(2):196–211. https://doi.org/10.1016/j.ekir.2018.11.005

    Article  PubMed  Google Scholar 

  69. Azzouz L, Cherry A, Riedl M, Khan M, Pluthero FG, Kahr WHA, Palaniyar N, Licht C (2018) Relative antibacterial functions of complement and NETs: NETs trap and complement effectively kills bacteria. Mol Immunol 97:71–81. https://doi.org/10.1016/j.molimm.2018.02.019

    Article  CAS  PubMed  Google Scholar 

  70. Remijsen Q, Kuijpers TW, Wirawan E, Lippens S, Vandenabeele P, Vanden Berghe T (2011) Dying for a cause: NETosis, mechanisms behind an antimicrobial cell death modality. Cell Death Differ 18(4):581–588. https://doi.org/10.1038/cdd.2011.1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Chen J, Zeng W, Pan W, Peng C, Zhang J, Su J, Long W, Zhao H, Zuo X, Xie X, Wu J, Nie L, Zhao HY, Wei HJ, Chen X (2018) Symptoms of systemic lupus erythematosus are diagnosed in leptin transgenic pigs. PLoS Biol 16(8):e2005354. https://doi.org/10.1371/journal.pbio.2005354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Zarkesh-Esfahani H, Pockley AG, Wu Z, Hellewell PG, Weetman AP, Ross RJ (2004) Leptin indirectly activates human neutrophils via induction of TNF-alpha. J Immunol 172(3):1809–1814

    Article  CAS  PubMed  Google Scholar 

  73. Santos FM, Telles RW, Lanna CC, Teixeira AL Jr, Miranda AS, Rocha NP, Ribeiro AL (2017) Adipokines, tumor necrosis factor and its receptors in female patients with systemic lupus erythematosus. Lupus 26(1):10–16. https://doi.org/10.1177/0961203316646463

    Article  CAS  PubMed  Google Scholar 

  74. Krysiak R, Handzlik-Orlik G, Okopien B (2012) The role of adipokines in connective tissue diseases. Eur J Nutr 51(5):513–528. https://doi.org/10.1007/s00394-012-0370-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Al-Rashed F, Ahmad Z, Iskandar MA, Tuomilehto J, Al-Mulla F, Ahmad R (2019) TNF-alpha induces a pro-inflammatory phenotypic shift in monocytes through ACSL1: relevance to metabolic inflammation. Cell Physiol Biochem 52(3):397–407. https://doi.org/10.33594/000000028

    Article  CAS  PubMed  Google Scholar 

  76. Locker F, Lang AA, Koller A, Lang R, Bianchini R, Kofler B (2015) Galanin modulates human and murine neutrophil activation in vitro. Acta Physiol (Oxford) 213(3):595–602. https://doi.org/10.1111/apha.12444

    Article  CAS  Google Scholar 

  77. Lakschevitz FS, Hassanpour S, Rubin A, Fine N, Sun C, Glogauer M (2016) Identification of neutrophil surface marker changes in health and inflammation using high-throughput screening flow cytometry. Exp Cell Res 342(2):200–209. https://doi.org/10.1016/j.yexcr.2016.03.007

    Article  CAS  PubMed  Google Scholar 

  78. Lee KH, Kronbichler A, Park DD, Park Y, Moon H, Kim H, Choi JH, Choi Y, Shim S, Lyu IS, Yun BH, Han Y, Lee D, Lee SY, Yoo BH, Lee KH, Kim TL, Kim H, Shim JS, Nam W, So H, Choi S, Lee S, Shin JI (2017) Neutrophil extracellular traps (NETs) in autoimmune diseases: a comprehensive review. Autoimmun Rev 16(11):1160–1173. https://doi.org/10.1016/j.autrev.2017.09.012

    Article  CAS  PubMed  Google Scholar 

  79. Souza-Almeida G, D’Avila H, Almeida PE, Luna-Gomes T, Liechocki S, Walzog B, Hepper I, Castro-Faria-Neto HC, Bozza PT, Bandeira-Melo C, Maya-Monteiro CM (2018) Leptin mediates in vivo neutrophil migration: involvement of tumor necrosis factor-alpha and CXCL1. Front Immunol 9:111. https://doi.org/10.3389/fimmu.2018.00111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Frasca D, Blomberg BB (2017) Adipose tissue inflammation induces B cell inflammation and decreases B cell function in aging. Front Immunol 8:1003. https://doi.org/10.3389/fimmu.2017.01003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Amarilyo G, Iikuni N, Shi FD, Liu A, Matarese G, La Cava A (2013) Leptin promotes lupus T-cell autoimmunity. Clin Immunol 149(3):530–533. https://doi.org/10.1016/j.clim.2013.09.002

    Article  CAS  PubMed  Google Scholar 

  82. La Cava A (2009) Lupus and T cells. Lupus 18(3):196–201. https://doi.org/10.1177/0961203308098191

    Article  PubMed  Google Scholar 

  83. Chen M, Chen X, Wan Q (2018) Altered frequency of Th17 and Treg cells in new-onset systemic lupus erythematosus patients. Eur J Clin Investig 48(11):e13012. https://doi.org/10.1111/eci.13012

    Article  CAS  Google Scholar 

  84. An N, Chen Y, Wang C, Yang C, Wu ZH, Xue J, Ye L, Wang S, Liu HF, Pan Q (2017) Chloroquine autophagic inhibition rebalances Th17/Treg-mediated immunity and ameliorates systemic lupus erythematosus. Cell Physiol Biochem 44(1):412–422. https://doi.org/10.1159/000484955

    Article  CAS  PubMed  Google Scholar 

  85. Lopez P, de Paz B, Rodriguez-Carrio J, Hevia A, Sanchez B, Margolles A, Suarez A (2016) Th17 responses and natural IgM antibodies are related to gut microbiota composition in systemic lupus erythematosus patients. Sci Rep 6:24072. https://doi.org/10.1038/srep24072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Koga T, Ichinose K, Tsokos GC (2017) T cells and IL-17 in lupus nephritis. Clin Immunol 185:95–99. https://doi.org/10.1016/j.clim.2016.04.010

    Article  CAS  PubMed  Google Scholar 

  87. Kuwabara T, Ishikawa F, Kondo M, Kakiuchi T (2017) The role of IL-17 and related cytokines in inflammatory autoimmune diseases. Mediat Inflamm 2017:3908061. https://doi.org/10.1155/2017/3908061

    Article  CAS  Google Scholar 

  88. Hsu HC, Yang P, Wang J, Wu Q, Myers R, Chen J, Yi J, Guentert T, Tousson A, Stanus AL, Le TVL, Lorenz RG, Xu H, Kolls JK, Carter RH, Chaplin DD, Williams RW, Mountz JD (2008) Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nat Immunol 9(2):166–175. https://doi.org/10.1038/ni1552

    Article  CAS  PubMed  Google Scholar 

  89. De la Cruz-Mosso U, Garcia-Iglesias T, Bucala R, Estrada-Garcia I, Gonzalez-Lopez L, Cerpa-Cruz S, Parra-Rojas I, Gamez-Nava JI, Perez-Guerrero EE, Munoz-Valle JF (2018) MIF promotes a differential Th1/Th2/Th17 inflammatory response in human primary cell cultures: predominance of Th17 cytokine profile in PBMC from healthy subjects and increase of IL-6 and TNF-alpha in PBMC from active SLE patients. Cell Immunol 324:42–49. https://doi.org/10.1016/j.cellimm.2017.12.010

    Article  CAS  PubMed  Google Scholar 

  90. Luzina IG, Atamas SP, Storrer CE, daSilva LC, Kelsoe G, Papadimitriou JC, Handwerger BS (2001) Spontaneous formation of germinal centers in autoimmune mice. J Leukoc Biol 70(4):578–584

    CAS  PubMed  Google Scholar 

  91. Nordstrom E, Abedi-Valugerdi M, Moller E (2000) Longevity of immune complexes and abnormal germinal centre formation in NZB mice. Scand J Immunol 52(5):477–482

    Article  CAS  PubMed  Google Scholar 

  92. Ferretti E, Ponzoni M, Doglioni C, Pistoia V (2016) IL-17 superfamily cytokines modulate normal germinal center B cell migration. J Leukoc Biol 100(5):913–918. https://doi.org/10.1189/jlb.1VMR0216-096RR

    Article  CAS  PubMed  Google Scholar 

  93. Pin RH, Reinblatt M, Fong Y (2004) Employing tumor hypoxia to enhance oncolytic viral therapy in breast cancer. Surgery 136(2):199–204. https://doi.org/10.1016/j.surg.2004.04.016

    Article  PubMed  Google Scholar 

  94. Shi GX, Harrison K, Wilson GL, Moratz C, Kehrl JH (2002) RGS13 regulates germinal center B lymphocytes responsiveness to CXC chemokine ligand (CXCL)12 and CXCL13. J Immunol 169(5):2507–2515

    Article  CAS  PubMed  Google Scholar 

  95. Terrier B, Costedoat-Chalumeau N, Garrido M, Geri G, Rosenzwajg M, Musset L, Klatzmann D, Saadoun D, Cacoub P (2012) Interleukin 21 correlates with T cell and B cell subset alterations in systemic lupus erythematosus. J Rheumatol 39(9):1819–1828. https://doi.org/10.3899/jrheum.120468

    Article  CAS  PubMed  Google Scholar 

  96. Kuchen S, Robbins R, Sims GP, Sheng C, Phillips TM, Lipsky PE, Ettinger R (2007) Essential role of IL-21 in B cell activation, expansion, and plasma cell generation during CD4+ T cell-B cell collaboration. J Immunol 179(9):5886–5896. https://doi.org/10.4049/jimmunol.179.9.5886

    Article  CAS  PubMed  Google Scholar 

  97. Nakou M, Papadimitraki E, Fanouriakis A, Bertsias G, Choulaki C, Goulidaki N, Sidiropoulos P, Boumpas D (2013) Interleukin-21 is increased in active systemic lupus erythematosus patients and contributes to the generation of plasma B cells. Clin Exp Rheumatol 31(2):172–179

    PubMed  Google Scholar 

  98. Rodriguez-Carrio J, Lopez P, Alperi-Lopez M, Caminal-Montero L, Ballina-Garcia FJ, Suarez A (2018) IRF4 and IRGs delineate clinically relevant gene expression signatures in systemic lupus erythematosus and rheumatoid arthritis. Front Immunol 9:3085. https://doi.org/10.3389/fimmu.2018.03085

    Article  CAS  PubMed  Google Scholar 

  99. Huber M, Brüstle A, Reinhard K, Guralnik A, Walter G, Mahiny A, von Löw E, Lohoff M (2008) IRF4 is essential for IL-21-mediated induction, amplification, and stabilization of the Th17. Proc Natl Acad Sci U S A 105(52):20846–20851. https://doi.org/10.1073/pnas.0809077106

    Article  PubMed  PubMed Central  Google Scholar 

  100. Rozo C, Chinenov Y, Maharaj RK, Gupta S, Leuenberger L, Kirou KA, Bykerk VP, Goodman SM, Salmon JE, Pernis AB (2017) Targeting the RhoA-ROCK pathway to reverse T-cell dysfunction in SLE. Ann Rheum Dis 76(4):740–747. https://doi.org/10.1136/annrheumdis-2016-209850

    Article  CAS  PubMed  Google Scholar 

  101. Xia LP, Li BF, Shen H, Lu J (2015) Interleukin-27 and interleukin-23 in patients with systemic lupus erythematosus: possible role in lupus nephritis. Scand J Rheumatol 44(3):200–205. https://doi.org/10.3109/03009742.2014.962080

    Article  CAS  PubMed  Google Scholar 

  102. Mok MY, Wu HJ, Lo Y, Lau CS (2010) The relation of interleukin 17 (IL-17) and IL-23 to Th1/Th2 cytokines and disease activity in systemic lupus erythematosus. J Rheumatol 37(10):2046–2052. https://doi.org/10.3899/jrheum.100293

    Article  PubMed  Google Scholar 

  103. Dai H, He F, Tsokos GC, Kyttaris VC (2017) IL-23 limits the production of IL-2 and promotes autoimmunity in lupus. J Immunol 199(3):903–910. https://doi.org/10.4049/jimmunol.1700418

    Article  CAS  PubMed  Google Scholar 

  104. Reis BS, Lee K, Fanok MH, Mascaraque C, Amoury M, Cohn LB, Rogoz A, Dallner OS, Moraes-Vieira PM, Domingos AI, Mucida D (2015) Leptin receptor signaling in T cells is required for Th17 differentiation. J Immunol 194(11):5253–5260. https://doi.org/10.4049/jimmunol.1402996

    Article  CAS  PubMed  Google Scholar 

  105. Gerriets VA, Danzaki K, Kishton RJ, Eisner W, Nichols AG, Saucillo DC, Shinohara ML, MacIver NJ (2016) Leptin directly promotes T-cell glycolytic metabolism to drive effector T-cell differentiation in a mouse model of autoimmunity. Eur J Immunol 46(8):1970–1983. https://doi.org/10.1002/eji.201545861

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Urushima H, Fujimoto M, Mishima T, Ohkawara T, Honda H, Lee H, Kawahata H, Serada S, Naka T (2017) Leucine-rich alpha 2 glycoprotein promotes Th17 differentiation and collagen-induced arthritis in mice through enhancement of TGF-beta-Smad2 signaling in naive helper T cells. Arthritis Res Ther 19(1):137. https://doi.org/10.1186/s13075-017-1349-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Chuang HC, Sheu WH, Lin YT, Tsai CY, Yang CY, Cheng YJ, Huang PY, Li JP, Chiu LL, Wang X, Xie M, Schneider MD, Tan TH (2014) HGK/MAP4K4 deficiency induces TRAF2 stabilization and Th17 differentiation leading to insulin resistance. Nat Commun 5:4602. https://doi.org/10.1038/ncomms5602

    Article  CAS  PubMed  Google Scholar 

  108. Deng J, Liu Y, Yang M, Wang S, Zhang M, Wang X, Ko KH, Hua Z, Sun L, Cao X, Lu L (2012) Leptin exacerbates collagen-induced arthritis via enhancement of Th17 cell response. Arthritis Rheum 64(11):3564–3573. https://doi.org/10.1002/art.34637

    Article  CAS  PubMed  Google Scholar 

  109. Yu Y, Liu Y, Shi FD, Zou H, Matarese G, La Cava A (2013) Cutting edge: leptin-induced RORgammat expression in CD4+ T cells promotes Th17 responses in systemic lupus erythematosus. J Immunol 190(7):3054–3058. https://doi.org/10.4049/jimmunol.1203275

    Article  CAS  PubMed  Google Scholar 

  110. Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y, Bordman Z, Fu J, Kim Y, Yen HR, Luo W, Zeller K, Shimoda L, Topalian SL, Semenza GL, Dang CV, Pardoll DM, Pan F (2011) Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell 146(5):772–784. https://doi.org/10.1016/j.cell.2011.07.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Martin JC, Baeten DL, Josien R (2014) Emerging role of IL-17 and Th17 cells in systemic lupus erythematosus. Clin Immunol 154(1):1–12. https://doi.org/10.1016/j.clim.2014.05.004

    Article  CAS  PubMed  Google Scholar 

  112. Sha Y, Markovic-Plese S (2016) Activated IL-1RI signaling pathway induces Th17 cell differentiation via interferon regulatory factor 4 signaling in patients with relapsing-remitting multiple sclerosis. Front Immunol 7:543. https://doi.org/10.3389/fimmu.2016.00543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Littman DR, Rudensky AY (2010) Th17 and regulatory T cells in mediating and restraining inflammation. Cell 140(6):845–858. https://doi.org/10.1016/j.cell.2010.02.021

    Article  CAS  PubMed  Google Scholar 

  114. Basu R, Hatton RD, Weaver CT (2013) The Th17 family: flexibility follows function. Immunol Rev 252(1):89–103. https://doi.org/10.1111/imr.12035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Bonelli M, Smolen JS, Scheinecker C (2010) Treg and lupus. Ann Rheum Dis 69(Suppl 1):i65–i66. https://doi.org/10.1136/ard.2009.117135

    Article  CAS  PubMed  Google Scholar 

  116. Mellor-Pita S, Citores MJ, Castejon R, Tutor-Ureta P, Yebra-Bango M, Andreu JL, Vargas JA (2006) Decrease of regulatory T cells in patients with systemic lupus erythematosus. Ann Rheum Dis 65(4):553–554. https://doi.org/10.1136/ard.2005.044974

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Lyssuk EY, Torgashina AV, Soloviev SK, Nassonov EL, Bykovskaia SN (2007) Reduced number and function of CD4+CD25highFoxP3+ regulatory T cells in patients with systemic lupus erythematosus. Adv Exp Med Biol 601:113–119

    Article  PubMed  Google Scholar 

  118. Lee JH, Wang LC, Lin YT, Yang YH, Lin DT, Chiang BL (2006) Inverse correlation between CD4(+) regulatory T-cell population and autoantibody levels in paediatric patients with systemic lupus erythematosus. Immunology 117(2):280–286. https://doi.org/10.1111/j.1365-2567.2005.02306.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Suarez A, Lopez P, Gomez J, Gutierrez C (2006) Enrichment of CD4+ CD25high T cell population in patients with systemic lupus erythematosus treated with glucocorticoids. Ann Rheum Dis 65(11):1512–1517. https://doi.org/10.1136/ard.2005.049924

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Sfikakis PP, Souliotis VL, Fragiadaki KG, Moutsopoulos HM, Boletis JN, Theofilopoulos AN (2007) Increased expression of the FoxP3 functional marker of regulatory T cells following B cell depletion with rituximab in patients with lupus nephritis. Clin Immunol 123(1):66–73. https://doi.org/10.1016/j.clim.2006.12.006

    Article  CAS  PubMed  Google Scholar 

  121. Azab NA, Bassyouni IH, Emad Y, Abd El-Wahab GA, Hamdy G, Mashahit MA (2008) CD4+CD25+ regulatory T cells (TREG) in systemic lupus erythematosus (SLE) patients: the possible influence of treatment with corticosteroids. Clin Immunol 127(2):151–157. https://doi.org/10.1016/j.clim.2007.12.010

    Article  CAS  PubMed  Google Scholar 

  122. Valencia X, Yarboro C, Illei G, Lipsky PE (2007) Deficient CD4+CD25high T regulatory cell function in patients with active systemic lupus erythematosus. J Immunol 178(4):2579–2588

    Article  CAS  PubMed  Google Scholar 

  123. Tao JH, Cheng M, Tang JP, Liu Q, Pan F, Li XP (2017) Foxp3, regulatory T cell, and autoimmune diseases. Inflammation 40(1):328–339. https://doi.org/10.1007/s10753-016-0470-8

    Article  CAS  PubMed  Google Scholar 

  124. Ohl K, Tenbrock K (2015) Regulatory T cells in systemic lupus erythematosus. Eur J Immunol 45(2):344–355. https://doi.org/10.1002/eji.201344280

    Article  CAS  PubMed  Google Scholar 

  125. Rodriguez-Perea AL, Arcia ED, Rueda CM, Velilla PA (2016) Phenotypical characterization of regulatory T cells in humans and rodents. Clin Exp Immunol 185(3):281–291. https://doi.org/10.1111/cei.12804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Gerli R, Nocentini G, Alunno A, Bocci EB, Bianchini R, Bistoni O, Riccardi C (2009) Identification of regulatory T cells in systemic lupus erythematosus. Autoimmun Rev 8(5):426–430. https://doi.org/10.1016/j.autrev.2009.01.004

    Article  CAS  PubMed  Google Scholar 

  127. Collison LW, Workman CJ, Kuo TT, Boyd K, Wang Y, Vignali KM, Cross R, Sehy D, Blumberg RS, Vignali DA (2007) The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450(7169):566–569. https://doi.org/10.1038/nature06306

    Article  CAS  PubMed  Google Scholar 

  128. Wong CK, Leung TF, Chu IM, Dong J, Lam YY, Lam CW (2015) Aberrant expression of regulatory cytokine IL-35 and pattern recognition receptor NOD2 in patients with allergic asthma. Inflammation 38(1):348–360. https://doi.org/10.1007/s10753-014-0038-4

    Article  CAS  PubMed  Google Scholar 

  129. Nakamura K, Kitani A, Strober W (2001) Cell contact-dependent immunosuppression by CD4(+)CD25(+) regulatory T cells is mediated by cell surface-bound transforming growth factor beta. J Exp Med 194(5):629–644. https://doi.org/10.1084/jem.194.5.629

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Grossman WJ, Verbsky JW, Barchet W, Colonna M, Atkinson JP, Ley TJ (2004) Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 21(4):589–601. https://doi.org/10.1016/j.immuni.2004.09.002

    Article  CAS  PubMed  Google Scholar 

  131. De Smedt T, Van Mechelen M, De Becker G, Urbain J, Leo O, Moser M (1997) Effect of interleukin-10 on dendritic cell maturation and function. Eur J Immunol 27(5):1229–1235. https://doi.org/10.1002/eji.1830270526

    Article  PubMed  Google Scholar 

  132. Pandiyan P, Zheng L, Ishihara S, Reed J, Lenardo MJ (2007) CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nat Immunol 8(12):1353–1362. https://doi.org/10.1038/ni1536

    Article  CAS  PubMed  Google Scholar 

  133. Oberle N, Eberhardt N, Falk CS, Krammer PH, Suri-Payer E (2007) Rapid suppression of cytokine transcription in human CD4+CD25 T cells by CD4+Foxp3+ regulatory T cells: independence of IL-2 consumption, TGF-beta, and various inhibitors of TCR signaling. J Immunol 179(6):3578–3587

    Article  CAS  PubMed  Google Scholar 

  134. Chavele KM, Ehrenstein MR (2011) Regulatory T-cells in systemic lupus erythematosus and rheumatoid arthritis. FEBS Lett 585(23):3603–3610. https://doi.org/10.1016/j.febslet.2011.07.043

    Article  CAS  PubMed  Google Scholar 

  135. Bopp T, Becker C, Klein M, Klein-Hessling S, Palmetshofer A, Serfling E, Heib V, Becker M, Kubach J, Schmitt S, Stoll S, Schild H, Staege MS, Stassen M, Jonuleit H, Schmitt E (2007) Cyclic adenosine monophosphate is a key component of regulatory T cell-mediated suppression. J Exp Med 204(6):1303–1310. https://doi.org/10.1084/jem.20062129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Borsellino G, Kleinewietfeld M, Di Mitri D, Sternjak A, Diamantini A, Giometto R, Hopner S, Centonze D, Bernardi G, Dell’Acqua ML, Rossini PM, Battistini L, Rotzschke O, Falk K (2007) Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 110(4):1225–1232. https://doi.org/10.1182/blood-2006-12-064527

    Article  CAS  PubMed  Google Scholar 

  137. Kobie JJ, Shah PR, Yang L, Rebhahn JA, Fowell DJ, Mosmann TR (2006) T regulatory and primed uncommitted CD4 T cells express CD73, which suppresses effector CD4 T cells by converting 5'-adenosine monophosphate to adenosine. J Immunol 177(10):6780–6786

    Article  CAS  PubMed  Google Scholar 

  138. Munn DH, Sharma MD, Mellor AL (2004) Ligation of B7-1/B7-2 by human CD4+ T cells triggers indoleamine 2,3-dioxygenase activity in dendritic cells. J Immunol 172(7):4100–4110. https://doi.org/10.4049/jimmunol.172.7.4100

    Article  CAS  PubMed  Google Scholar 

  139. Hayashi T, Hasegawa K, Adachi C (2005) Elimination of CD4(+)CD25(+) T cell accelerates the development of glomerulonephritis during the preactive phase in autoimmune-prone female NZB x NZW F-1 mice. Int J Exp Pathol 86(5):289–296. https://doi.org/10.1111/j.0959-9673.2005.00438.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Wang X, Qiao Y, Yang L, Song S, Han Y, Tian Y, Ding M, Jin H, Shao F, Liu A (2017) Leptin levels in patients with systemic lupus erythematosus inversely correlate with regulatory T cell frequency. Lupus 26(13):1401–1406. https://doi.org/10.1177/0961203317703497

    Article  CAS  PubMed  Google Scholar 

  141. Matarese G, Di Giacomo A, Sanna V, Lord GM, Howard JK, Di Tuoro A, Bloom SR, Lechler RI, Zappacosta S, Fontana S (2001) Requirement for leptin in the induction and progression of autoimmune encephalomyelitis. J Immunol 166(10):5909–5916

    Article  CAS  PubMed  Google Scholar 

  142. Matarese G, Carrieri PB, Montella S, De Rosa V, La Cava A (2010) Leptin as a metabolic link to multiple sclerosis. Nat Rev Neurol 6(8):455–461. https://doi.org/10.1038/nrneurol.2010.89

    Article  CAS  PubMed  Google Scholar 

  143. Wei R, Hu Y, Dong F, Xu X, Hu A, Gao G (2016) Hepatoma cell-derived leptin downregulates the immunosuppressive function of regulatory T-cells to enhance the anti-tumor activity of CD8+ T-cells. Immunol Cell Biol 94(4):388–399. https://doi.org/10.1038/icb.2015.110

    Article  CAS  PubMed  Google Scholar 

  144. Zhou H, Shang C, Wang M, Shen T, Kong L, Yu C, Ye Z, Luo Y, Liu L, Li Y, Huang S (2016) Ciclopirox olamine inhibits mTORC1 signaling by activation of AMPK. Biochem Pharmacol 116:39–50. https://doi.org/10.1016/j.bcp.2016.07.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Zeng H, Yang K, Cloer C, Neale G, Vogel P, Chi H (2013) mTORC1 couples immune signals and metabolic programming to establish T(reg)-cell function. Nature 499(7459):485–490. https://doi.org/10.1038/nature12297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Moraes-Vieira PM, Larocca RA, Bassi EJ, Peron JP, Andrade-Oliveira V, Wasinski F, Araujo R, Thornley T, Quintana FJ, Basso AS, Strom TB, Camara NO (2014) Leptin deficiency impairs maturation of dendritic cells and enhances induction of regulatory T and Th17 cells. Eur J Immunol 44(3):794–806. https://doi.org/10.1002/eji.201343592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Kucharska AM, Pyrzak B, Demkow U (2015) Regulatory T cells in obesity. Noncommunicable Diseases 866:35–40. https://doi.org/10.1007/5584_2015_147

    Article  Google Scholar 

  148. Han S, Zhuang H, Xu Y, Lee P, Li Y, Wilson JC, Vidal O, Choi HS, Sun Y, Yang LJ, Reeves WH (2015) Maintenance of autoantibody production in pristane-induced murine lupus. Arthritis Res Ther 17:384. https://doi.org/10.1186/s13075-015-0886-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Wen J, Stock AD, Chalmers SA, Putterman C (2016) The role of B cells and autoantibodies in neuropsychiatric lupus. Autoimmun Rev 15(9):890–895. https://doi.org/10.1016/j.autrev.2016.07.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Cassia M, Alberici F, Gallieni M, Jayne D (2017) Lupus nephritis and B-cell targeting therapy. Expert Rev Clin Immunol 13(10):951–962. https://doi.org/10.1080/1744666X.2017.1366855

    Article  CAS  PubMed  Google Scholar 

  151. Chan OT, Madaio MP, Shlomchik MJ (1999) The central and multiple roles of B cells in lupus pathogenesis. Immunol Rev 169:107–121

    Article  CAS  PubMed  Google Scholar 

  152. Wen J, Chen CH, Stock A, Doerner J, Gulinello M, Putterman C (2016) Intracerebroventricular administration of TNF-like weak inducer of apoptosis induces depression-like behavior and cognitive dysfunction in non-autoimmune mice. Brain Behav Immun 54:27–37. https://doi.org/10.1016/j.bbi.2015.12.017

    Article  CAS  PubMed  Google Scholar 

  153. Dantzer R (2009) Cytokine, sickness behavior, and depression. Immunol Allergy Clin N Am 29(2):247–264. https://doi.org/10.1016/j.iac.2009.02.002

    Article  Google Scholar 

  154. Giles JR, Kashgarian M, Koni PA, Shlomchik MJ (2015) B cell-specific MHC class II deletion reveals multiple nonredundant roles for B cell antigen presentation in murine lupus. J Immunol 195(6):2571–2579. https://doi.org/10.4049/jimmunol.1500792

    Article  CAS  PubMed  Google Scholar 

  155. Giltiay NV, Shu GL, Shock A, Clark EA (2017) Targeting CD22 with the monoclonal antibody epratuzumab modulates human B-cell maturation and cytokine production in response to Toll-like receptor 7 (TLR7) and B-cell receptor (BCR) signaling. Arthritis Res Ther 19(1):91. https://doi.org/10.1186/s13075-017-1284-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Barr TA, Shen P, Brown S, Lampropoulou V, Roch T, Lawrie S, Fan B, O’Connor RA, Anderton SM, Bar-Or A, Fillatreau S, Gray D (2012) B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6-producing B cells. J Exp Med 209(5):1001–1010. https://doi.org/10.1084/jem.20111675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Lampropoulou V, Hoehlig K, Roch T, Neves P, Calderon Gomez E, Sweenie CH, Hao Y, Freitas AA, Steinhoff U, Anderton SM, Fillatreau S (2008) TLR-activated B cells suppress T cell-mediated autoimmunity. J Immunol 180(7):4763–4773

    Article  CAS  PubMed  Google Scholar 

  158. Sieber J, Daridon C, Fleischer SJ, Fleischer V, Hiepe F, Alexander T, Heine G, Burmester GR, Fillatreau S, Dörner T (2014) Active systemic lupus erythematosus is associated with a reduced cytokine production by B cells in response to TLR9 stimulation. Arthritis Res Ther 16:477

    Article  PubMed  PubMed Central  Google Scholar 

  159. Glaum MC, Narula S, Song D, Zheng Y, Anderson AL, Pletcher CH, Levinson AI (2009) Toll-like receptor 7-induced naive human B-cell differentiation and immunoglobulin production. J Allergy Clin Immunol 123(1):224–230 e224. https://doi.org/10.1016/j.jaci.2008.09.018

    Article  CAS  PubMed  Google Scholar 

  160. Agrawal S, Gollapudi S, Su H, Gupta S (2011) Leptin activates human B cells to secrete TNF-alpha, IL-6, and IL-10 via JAK2/STAT3 and p38MAPK/ERK1/2 signaling pathway. J Clin Immunol 31(3):472–478. https://doi.org/10.1007/s10875-010-9507-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Tanaka M, Suganami T, Kim-Saijo M, Toda C, Tsuiji M, Ochi K, Kamei Y, Minokoshi Y, Ogawa Y (2011) Role of central leptin signaling in the starvation-induced alteration of B-cell development. J Neurosci 31(23):8373–8380. https://doi.org/10.1523/Jneurosci.6562-10.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Lam QLK, Wang SJ, Ko OKH, Kincade PW, Lu LW (2010) Leptin signaling maintains B-cell homeostasis via induction of Bcl-2 and Cyclin D1. P Natl Acad Sci USA 107(31):13812–13817. https://doi.org/10.1073/pnas.1004185107

    Article  Google Scholar 

Download references

Funding

This work was supported by the National Natural Science Foundation of China (grant nos. 81671606, 81501345), Natural Science Foundation of Liaoning Province (grant no. 20180550789), College Scientific Research Project of Education Department of Liaoning Province (grant no. LQ2017007), and Dalian Medical University Foundation for Teaching Reform Project of Undergraduate Innovative Talents Training (grant no. 111507010322).

Author information

Authors and Affiliations

  1. Department of Immunology, College of Basic Medical Science, Dalian Medical University, Liaoning, China

    Qihang Yuan, Xia Li & Jing Wei

  2. Department of Immunology and Rheumatology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Jiangsu, China

    Haifeng Chen

Authors
  1. Qihang Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Haifeng Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xia Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jing Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors alone are responsible for the content and writing of the paper. Qihang Yuan contributed to the design of the study, collection and interpretation of data, and drafting and revising the manuscript. Haifeng Chen was responsible for the interpretation of data and drafting the manuscript. Xia Li and Jing Wei conceived the study and reviewed/edited the manuscript.

Corresponding authors

Correspondence to Xia Li or Jing Wei.

Ethics declarations

Disclosures

None.

Ethical approval

Submitted paper is a review of relevant literature. This article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yuan, Q., Chen, H., Li, X. et al. Leptin: an unappreciated key player in SLE. Clin Rheumatol 39, 305–317 (2020). https://doi.org/10.1007/s10067-019-04831-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10067-019-04831-8

Keywords

Search

Navigation