The role of IL-17 in systemic lupus erythematosus and its potential as a therapeutic target

ABSTRACT

Introduction: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibodies production and immune complex deposition with systemic clinical manifestations. Interleukin (IL)-17-producing cells play a crucial role in disease pathogenesis and represent an attractive therapeutic target.

Areas covered: This review provides an update on the possibility of targeting IL-17 in SLE. The rational for this approach as well as currently available and future targets are discussed.

Expert opinion: Although human expression studies and animal models indicate that IL-17 blocking may be a promising therapeutic strategy for SLE, direct evidence for IL-17 inhibition in SLE patients is unavailable. Biologic therapies and small-molecule drugs that target IL-17 production are required for the achievement of a favorable clinical effect in SLE patients.

KEYWORDS:

• T cells
• systemic lupus erythematosus (SLE)
• lupus nephritis
• immune responses
• interleukin (IL)-17

Article highlights

• T cells serve as the commander of the immune response in SLE pathogenesis, presenting multiple opportunities for the identification and exploitation of therapeutic targets.

• The imbalance of Th17/Treg is attributable to decreased IL-2 production and contributes to organ inflammation and damage in SLE patients.

• Either the percentage of circulating Th17 cells or the concentration of serum IL-17A correlates positively with disease activity in SLE.

• DN T cells and Th17 cells produce increased amounts of IL-17 in the kidneys in lupus-prone mice and SLE patients.

• SLE T cells are characterized by several aberrant signaling pathways manifested with the abnormal expression of PP2A, ROCK, CREM, CaMK4, and mTORC1, all of which are shown to lead to skewed Th17 differentiation.

• Efficacy and safety of ustekinumab, an anti-IL-12/23 p40 monoclonal antibody, has been demonstrated in SLE patients; however, its efficacy in LN remains unclear.

• Human expression studies, animal models, and clinical trials indicate that IL-17 blockade may become a promising therapeutic strategy for SLE.

Declaration of interest

GC Tsokos is on the SAB of Silicon Therapeutics and ABRO. Work in the lab of GC Tsokos has been funded by NIH grants and the Lupus Insight Award. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by grants from the Leading Initiative for Excellent Young Researchers of the Ministry of Education, Culture, Sports, Science and Technology (to T Koga, no. 16810055).