The involvement of the interleukin (IL)-17 axis in many inflammatory and autoimmune diseases is now well established, and this has led to the development of successful targeted therapies. Its role in systemic lupus erythematosus (SLE) is less described, since SLE is characterized by the impairment of many other immune actors. However, results from animal models and patients strongly suggest that IL-17 and its producing cells are involved in SLE pathogenesis. Circulating levels of IL-17 are increased in lupus, and tissue staining shows the presence of IL-17-producing cells in organ lesions. Through different mechanisms, the IL-17 axis promotes autoantibody production, immune complex deposition, complement activation and then tissue damage. There are also many interactions with other immune and non-immune actors, which account for the broad spectrum of clinical manifestations and disease heterogeneity. SLE treatment faces challenges with many disappointing trials and persistent unmet needs. The identification of subsets of SLE patients with an IL-17-driven disease now constitutes the key priority before starting trials. More preclinical studies are needed to improve the selection of the right patients able to respond and tolerate the many inhibitors that are already available.
MiossecPKollsJK. Targeting IL-17 and TH17 cells in chronic inflammation. Nat Rev Drug Discov2012; 11: 763–776.
2.
BeringerAMiossecP. Systemic effects of IL-17 in inflammatory arthritis. Nat Rev Rheumatol2019; 15: 491–501.
3.
BeringerAMiossecP. IL-17 and IL-17-producing cells and liver diseases, with focus on autoimmune liver diseases. Autoimmun Rev2018; 17: 1176–1185.
4.
KogaTIchinoseKKawakamiATsokosGC. The role of IL-17 in systemic lupus erythematosus and its potential as a therapeutic target. Expert Rev Clin Immunol2019; 15: 629–637.
5.
RahmanAIsenbergDA. Systemic lupus erythematosus. N Engl J Med2008; 358: 929–939.
6.
KiriakidouMCottonDTaichmanDWilliamsS. Systemic lupus erythematosus. Ann Intern Med2013; 159: ITC4-1–ITC4-1.
GattoMZenMIaccarinoLDoriaA. New therapeutic strategies in systemic lupus erythematosus management. Nat Rev Rheumatol2019; 15: 30–48.
9.
RobertMMiossecP. IL-17 in rheumatoid arthritis and precision medicine: from synovitis expression to circulating bioactive levels. Front Med (Lausanne)2018; 5: 364–364.
10.
RouvierELucianiMFMatteiMGDenizotFGolsteinP. CTLA-8, cloned from an activated T cell, bearing AU-rich messenger RNA instability sequences, and homologous to a herpesvirus saimiri gene. J Immunol1993; 150: 5445–5456.
11.
YaoZPainterSLFanslowWC, et al.Human IL-17: a novel cytokine derived from T cells. J Immunol1995; 155: 5483–5486.
12.
BeringerANoackMMiossecP. IL-17 in chronic inflammation: from discovery to targeting. Trends Mol Med2016; 22: 230–241.
13.
LeeJHoWHMaruokaM, et al.IL-17E, a novel proinflammatory ligand for the IL-17 receptor homolog IL-17Rh1. J Biol Chem2001; 276: 1660–1664.
14.
LavocatFNdongo-ThiamNMiossecP. Interleukin-25 produced by synoviocytes has anti-inflammatory effects by acting as a receptor antagonist for interleukin-17A function. Front Immunol2017; 8: 647–647.
15.
FallonPGBallantyneSJManganNE, et al.Identification of an interleukin (IL)-25-dependent cell population that provides IL-4, IL-5, and IL-13 at the onset of helminth expulsion. J Exp Med2006; 203: 1105–1116.
16.
BallantyneSJBarlowJLJolinHE, et al.Blocking IL-25 prevents airway hyperresponsiveness in allergic asthma. J Allergy Clin Immunol2007; 120: 1324–1331.
17.
AarvakTChabaudMMiossecPNatvigJB. IL-17 is produced by some proinflammatory Th1/Th0 cells but not by Th2 cells. J Immunol1999; 162: 1246–1251.
18.
ParkHLiZYangXO, et al.A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol2005; 6: 1133–1141.
19.
NoackMMiossecP. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun Rev2014; 13: 668–677.
20.
CrispinJCOukkaMBaylissG, et al.Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys. J Immunol2008; 181: 8761–8766.
21.
NoordenbosTBlijdorpIChenS, et al.Human mast cells capture, store, and release bioactive, exogenous IL-17A. J Leukoc Biol2016; 100: 453–462.
22.
LinAMRubinCJKhandpurR, et al.Mast cells and neutrophils release IL-17 through extracellular trap formation in psoriasis. J Immunol2011; 187: 490–500.
23.
YaoZFanslowWCSeldinMF, et al.Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity1995; 3: 811–821.
24.
RobertMMiossecP. Effects of Interleukin 17 on the cardiovascular system. Autoimmun Rev2017; 16: 984–991.
25.
CrispinJCKyttarisVCTerhorstCTsokosGC. T cells as therapeutic targets in SLE. Nat Rev Rheumatol2010; 6: 317–325.
26.
VincentFBMorandEFSchneiderPMackayF. The BAFF/APRIL system in SLE pathogenesis. Nat Rev Rheumatol2014; 10: 365–373.
27.
SchmidtTPaustHJKrebsCF, et al.Function of the Th17/interleukin-17A immune response in murine lupus nephritis. Arthritis Rheumatol2015; 67: 475–487.
28.
ZhangZKyttarisVCTsokosGC. The role of IL-23/IL-17 axis in lupus nephritis. J Immunol2009; 183: 3160–3169.
29.
KidoMTakeuchiSSugiyamaN, et al.T cell-specific overexpression of interleukin-27 receptor alpha subunit (WSX-1) prevents spontaneous skin inflammation in MRL/lpr mice. Br J Dermatol2011; 164: 1214–1220.
30.
HsuHCYangPWangJ, et al.Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nat Immunol2008; 9: 166–175.
31.
WenZXuLXuWYinZGaoXXiongS. Interleukin-17 expression positively correlates with disease severity of lupus nephritis by increasing anti-double-stranded DNA antibody production in a lupus model induced by activated lymphocyte derived DNA. PLoS One2013; 8: e58161–e58161.
32.
LeeSYLeeSHSeoHB, et al.Inhibition of IL-17 ameliorates systemic lupus erythematosus in Roquin(san/san) mice through regulating the balance of TFH cells, GC B cells, Treg and Breg. Sci Rep2019; 9: 5227–5227.
33.
HeJZhangXWeiY, et al.Low-dose interleukin-2 treatment selectively modulates CD4( + ) T cell subsets in patients with systemic lupus erythematosus. Nat Med2016; 22: 991–993.
MackayFWoodcockSALawtonP, et al.Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J Exp Med1999; 190: 1697–1710.
36.
Lai Kwan LamQKing Hung KoOZhengBJLuL. Local BAFF gene silencing suppresses Th17-cell generation and ameliorates autoimmune arthritis. Proc Natl Acad Sci U S A2008; 105: 14993–14998.
37.
TalaatRMMohamedSFBassyouniIHRaoufAA. Th1/Th2/Th17/Treg cytokine imbalance in systemic lupus erythematosus (SLE) patients: correlation with disease activity. Cytokine2015; 72: 146–153.
38.
WongCKHoCYLiEKLamCW. Elevation of proinflammatory cytokine (IL-18, IL-17, IL-12) and Th2 cytokine (IL-4) concentrations in patients with systemic lupus erythematosus. Lupus2000; 9: 589–593.
39.
WongCKLitLCTamLSLiEKWongPTLamCW. Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus: implications for Th17-mediated inflammation in auto-immunity. Clin Immunol2008; 127: 385–393.
40.
VincentFBNorthcottMHoiAMackayFMorandEF. Clinical associations of serum interleukin-17 in systemic lupus erythematosus. Arthritis Res Ther2013; 15: R97–R97.
41.
WuYCaiBZhangJ, et al.IL-1beta and IL-6 are highly expressed in RF + IgE + systemic lupus erythematous subtype. J Immunol Res2017; 2017: 5096741–5096741.
42.
ShahinDEl-FarahatyRMHoussenME, et al.Serum 25-OH vitamin D level in treatment-naive systemic lupus erythematosus patients: relation to disease activity, IL-23 and IL-17. Lupus2017; 26: 917–926.
43.
ChenSYLiuMFKuoPYWangCR. Upregulated expression of STAT3/IL-17 in patients with systemic lupus erythematosus. Clin Rheumatol2019; 38: 1361–1366.
44.
Abdel GalilSMEzzeldinNEl-BoshyME. The role of serum IL-17 and IL-6 as biomarkers of disease activity and predictors of remission in patients with lupus nephritis. Cytokine2015; 76: 280–287.
45.
ZickertAAmoudruzPSundstromYRonnelidJMalmstromVGunnarssonI. IL-17 and IL-23 in lupus nephritis - association to histopathology and response to treatment. BMC Immunol2015; 16: 7–7.
46.
DongGYeRShiW, et al.IL-17 induces autoantibody overproduction and peripheral blood mononuclear cell overexpression of IL-6 in lupus nephritis patients. Chin Med J (Engl)2003; 116: 543–548.
47.
KurasawaKHiroseKSanoH, et al.Increased interleukin-17 production in patients with systemic sclerosis. Arthritis Rheum2000; 43: 2455–2463.
48.
RaymondWOstli-EilertsenGGriffithsSNossentJ. IL-17A levels in systemic lupus erythematosus associated with inflammatory markers and lower rates of malignancy and heart damage: evidence for a dual role. Eur J Rheumatol2017; 4: 29–35.
49.
Ndongo-ThiamNMiossecP. A cell-based bioassay for circulating bioactive IL-17: application to destruction in rheumatoid arthritis. Ann Rheum Dis2015; 74: 1629–1631.
50.
YangJChuYYangX, et al.Th17 and natural Treg cell population dynamics in systemic lupus erythematosus. Arthritis Rheum2009; 60: 1472–1483.
51.
CerveraRKhamashtaMAFontJ, et al.Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine (Baltimore)2003; 82: 299–308.
52.
WangYItoSChinoY, et al.Laser microdissection-based analysis of cytokine balance in the kidneys of patients with lupus nephritis. Clin Exp Immunol2010; 159: 1–10.
53.
YaziciMUOrhanDKaleGBesbasNOzenS. Studying IFN-gamma, IL-17 and FOXP3 in pediatric lupus nephritis. Pediatr Nephrol2014; 29: 853–862.
54.
ChenDYChenYMWenMCHsiehTYHungWTLanJL. The potential role of Th17 cells and Th17-related cytokines in the pathogenesis of lupus nephritis. Lupus2012; 21: 1385–1396.
55.
OhSHRohHJKwonJE, et al.Expression of interleukin-17 is correlated with interferon-alpha expression in cutaneous lesions of lupus erythematosus. Clin Exp Dermatol2011; 36: 512–520.
56.
VillanuevaEYalavarthiSBerthierCC, et al.Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus. J Immunol2011; 187: 538–552.
57.
ShivakumarSTsokosGCDattaSK. T cell receptor alpha/beta 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 Immunol1989; 143: 103–112.
58.
LopezPRodriguez-CarrioJCaminal-MonteroLMozoLSuarezA. A pathogenic IFNalpha, BLyS and IL-17 axis in systemic lupus erythematosus patients. Sci Rep2016; 6: 20651–20651.
59.
DoreauABelotABastidJ, et al.Interleukin 17 acts in synergy with B cell-activating factor to influence B cell biology and the pathophysiology of systemic lupus erythematosus. Nat Immunol2009; 10: 778–785.
60.
EljaafariATartelinMLAissaouiH, et al.Bone marrow-derived and synovium-derived mesenchymal cells promote Th17 cell expansion and activation through caspase 1 activation: contribution to the chronicity of rheumatoid arthritis. Arthritis Rheum2012; 64: 2147–2157.
61.
FiresteinGS. Evolving concepts of rheumatoid arthritis. Nature2003; 423: 356–361.
62.
NestleFOKaplanDHBarkerJ. Psoriasis. N Engl J Med2009; 361: 496–509.
63.
ValenciaXYarboroCIlleiGLipskyPE. Deficient CD4 + CD25high T regulatory cell function in patients with active systemic lupus erythematosus. J Immunol2007; 178: 2579–2588.
64.
YanBYeSChenGKuangMShenNChenS. Dysfunctional CD4 + ,CD25 + regulatory T cells in untreated active systemic lupus erythematosus secondary to interferon-alpha-producing antigen-presenting cells. Arthritis Rheum2008; 58: 801–812.
65.
Linker-IsraeliMDeansRJWallaceDJPrehnJOzeri-ChenTKlinenbergJR. Elevated levels of endogenous IL-6 in systemic lupus erythematosus. A putative role in pathogenesis.J Immunol1991; 147: 117–123.
66.
KogaTIchinoseKTsokosGC. T cells and IL-17 in lupus nephritis. Clin Immunol2017; 185: 95–99.
67.
BakshiJSeguraBTWincupCRahmanA. Unmet needs in the pathogenesis and treatment of systemic lupus erythematosus. Clin Rev Allergy Immunol2018; 55: 352–367.
68.
ChabaudMDurandJMBuchsN, et al.Human interleukin-17: A T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis Rheum1999; 42: 963–970.
69.
Von Spee-MayerCSiegertEAbdiramaD, et al.Low-dose interleukin-2 selectively corrects regulatory T cell defects in patients with systemic lupus erythematosus. Ann Rheum Dis2016; 75: 1407–1415.
70.
MiossecP. Update on interleukin-17: a role in the pathogenesis of inflammatory arthritis and implication for clinical practice. RMD Open2017; 3: e000284–e000284.
71.
CarrascosaJMDel-AlcazarE. New therapies versus first-generation biologic drugs in psoriasis: a review of adverse events and their management. Expert Rev Clin Immunol2018; 14: 259–273.
72.
FragoulisGESiebertSMcInnesIB. Therapeutic targeting of IL-17 and IL-23 cytokines in immune-mediated diseases. Annu Rev Med2016; 67: 337–353.
73.
LebwohlMGPappKAMarangellLB, et al.Psychiatric adverse events during treatment with brodalumab: analysis of psoriasis clinical trials. J Am Acad Dermatol2018; 78: 81–89.e5.
74.
SatohYNakanoKYoshinariH, et al.A case of refractory lupus nephritis complicated by psoriasis vulgaris that was controlled with secukinumab. Lupus2018; 27: 1202–1206.
75.
De SouzaAAli-ShawTStroberBEFranksJrAG. Successful treatment of subacute lupus erythematosus with ustekinumab. Arch Dermatol2011; 147: 896–898.
76.
Van VollenhovenRFHahnBHTsokosGC, et al.Efficacy and safety of ustekinumab, an IL-12 and IL-23 inhibitor, in patients with active systemic lupus erythematosus: results of a multicentre, double-blind, phase 2, randomised, controlled study. Lancet2018; 392: 1330–1339.
77.
ShinJI. Induction of severe systemic lupus erythematosus by TNF blockade and response to an anti-IL-6 strategy: role of IL-17?J Allergy Clin Immunol2013; 132: 1257–1257.
78.
HumrichJYRiemekastenG. Clinical trials: the rise of IL-2 therapy – a novel biologic treatment for SLE. Nat Rev Rheumatol2016; 12: 695–696.
