T cells and IL-17 in Lupus Nephritis

Abstract

Systemic lupus erythematosus (SLE) is a complicated autoimmune disorder characterized by autoantibodies production, immune complex formation, and immune dysregulation, resulting in damage of multiple organs including the kidney. Lupus nephritis (LN) is the most common severe manifestation of SLE involving the majority of patients. Even though there are a number of reports indicating that interleukin-17 (IL-17) and Th17 cells play important roles in the pathogenesis of LN, the precise molecular mechanisms underline the development of LN have not been totally elucidated. In this review, we briefly summarize general characteristics of T and IL-17 cells in SLE. In addition, we discuss in detail T cell signaling pathways which control IL-17 production in patients with LN and in glomerulonephritis in lupus-prone mice. A better understanding of signaling and gene regulation defects in LN will lead to the identification of novel therapeutic targets and predictive biomarkers for diagnosis and prognosis of this disease.

1. Introduction

Systemic lupus erythematosus (SLE) is an autoimmune disorder of unknown cause that can affect every organ [1]. In particular, lupus nephritis (LN) is one of the most serious manifestations of SLE and the pathogenesis of LN involves a variety of mechanisms [2]. Even though it is considered that dendritic, B, and plasma cells, autoantibodies and complement contribute to the development of LN [3–6], T cell-medicated autoimmunity and glomerular injury are critical for persistent renal damage closely related to impaired quality of life [7, 8]. In addition, recent studies in human SLE and animal models indicate a central role for interleukin-17 (IL-17) in the pathogenesis of LN [9, 10]. Treatment of LN varies with the type of disease based on histological findings classified according to the International Society of Nephrology/Renal Pathology Society (ISN/RPS) criteria [11]. Even though combined immunosuppressive therapy is indicated in patients with diffuse and focal proliferative LN and in many patients with lupus membranous nephropathy [12, 13], there is no optimal treatment for all patients with LN. Accordingly, it is quite important to understand the molecular mechanisms by which T cells and IL-17 induce inflammation that trigger LN development. In addition, better understanding of T cell function and IL-17 production may lead to identification of useful biomarkers for this disease.

In this review, we discuss the evidence that links T cells and IL-17 to LN in both humans and lupus-prone mice and describe recent advances in T cell signaling pathways that lead to IL-17 production in LN. Data indicates that an imbalance between Th17 cells and Tregs along with IL-17-driven inflammation play an important role in the damage of the kidney.

2. T cells in SLE

T cells are important players involved in the development and progression of LN in lupus prone mice and SLE patients [14]. Indeed, T cells from patients with SLE present aberrant signaling upon TCR engagement and have an altered gene expression profile [15]. Depletion of T cells or blocking T-cell activation mitigates development of nephritis in lupus prone mice [16, 17]. Of note, the balance between Th17 cells and Tregs is crucially involved in SLE pathogenesis. Limited Treg numbers [18, 19] and impaired function [20] have been observed in patients with SLE, and these defects have been associated with increased lupus disease activity [18]. This imbalance could be caused by deficient IL-2 production since IL-2 is necessary for the maintenance of regulatory T cells and inhibition of Th17 differentiation [21, 22].

Importantly, T cells from lupus-prone mice as well as SLE patients exhibit impaired IL-2 production [1, 23–26] and it is partly attributed to the unbalanced activation of cAMP response element binding protein (CREB) and cAMP response element modulator (CREM)α. Increased activation of CREMα, along with a reciprocal decrease in activated CREB, results in impaired IL-2 production by T cells from patients with SLE [27, 28]. In addition, it has been reported that the aberrant functions of NF-κB and activator protein 1 (AP1) in SLE T cells contribute to decreased IL2 transcription [29, 30]. More recently, our lab has reported that administration of low dose IL-2 by using an inducible recombinant adeno-associated virus vector to lupus-prone mice results in increased Treg cell numbers and function, suppressed IL-17 production and tissue damage of kidneys [31]. Taken together, limited IL-2 levels skew the balance between Tregs and Th17 in favor of the latter (Figure 1).

Figure 1.

Lupus patients have an imbalance between Th17 and Treg cells. SLE: Systemic lupus erythematosus, TCR: T cell receptor, Th: T helper, Treg: regulatory T cell.

3. IL-17 in SLE

IL-17 has a potential to induce the production of additional inflammatory cytokines and chemokines and to promote recruitment of inflammatory cells such as monocytes and neutrophils to the inflamed organ [32, 33]. It is a key cytokine involved in the pathogenesis of autoimmune diseases including SLE [10, 33, 34]. Increased number of Th17 cells as well as high serum levels of IL-17 has been demonstrated in SLE patients [35–37]. Although IL-17 is the main cytokine produced by Th17 cells [33], it is also produced by other subsets of T cells including T-cell receptor (TCR)γδ and TCRαβ double negative (DN) T-cells (CD3⁺CD4⁻CD8⁻), macrophages and neutrophils [38, 39]. In addition to IL-17, IL-23 was also found to be crucial for the development of various autoimmune diseases in murine models [40–42] and in humans [43] by promoting Th17 cell–mediated tissue inflammation. There is accumulating evidence indicating the importance of IL-23 in patients with SLE [44–46]. Of note, our group has shown that clinical and pathology findings of LN are mitigated in lupus prone mice with IL-23 receptor deficiency [47] or treated with an anti-IL23 antibody [48]. In clinical settings, trial studies showed the efficacy and safely of treatment with ustekinumab, a human monoclonal antibody that binds to the p40 subunit of IL-23 in subacute cutaneous lupus [49], psoriasis [50], and psoriatic arthritis [51].

Collectively, these findings suggest a critical role of IL-23/IL-17 axis in the pathogenesis of SLE. Further studies are needed to clarify whether IL-23/ IL-17 could be useful in predicting long-term prognosis and its possibility of targets for new treatment strategies in SLE.

4. The role of T cells and IL-17 in lupus nephritis

It has been demonstrated that high levels of IL-17 predict poor histopathological outcome after immunosuppressive therapy in patients with LN [45]. Moreover, it has been reported that the urinary expression of Th17-related genes including IL17 and IL23 is increased in SLE patients and associated with the activity of LN [52].

Our group has proposed that DN T-cells infiltrate the kidneys of patients with LN and reresent the major source for IL-17 [38]. In line with this finding, it has also been shown that DN T-cells as well as Th17 cells produces increased amounts of IL-17 and IFN-γ in kidneys in lupus-prone mice [28]. Even though the precise molecular mechanisms which underline T cell or IL-17 dependent tissue damage of LN are not totally elucidated, there have been some novel findings which demonstrate the contribution of T cell signaling pathways to the expression of LN.

5. Aberrant T cell signaling in lupus nephritis

5.1. Protein phosphatase 2A (PP2A)

Protein phosphatase 2A (PP2A) is a multifunctional serine/threonine phosphatase involved in essential cellular processes. Increased expression of PP2A contributes to the dephosphorylation of a number of molecules including Elf-1, SP1, MEK, and CREB and thus plays as a critical role in aberrant T cell function [53–56]. Our group has shown that expression and activity of its catalytic subunit (PP2Ac) is increased in T cells from patients with SLE [55, 56] and that transgenic mice overexpressing PP2Ac in T cells develop glomerulonephritis resulting from increased production of IL-17A and IL-17F [57]. Accordingly, dysregulation of PP2Ac contributes to the pathogenesis of LN by promoting the inflammatory and migration capacity of IL-17 producing T cells.

5.2. Rho-associated protein kinase (ROCK)

Rho-associated protein kinase (ROCK) is a serine-threonine kinase involved mainly in regulating cell migration including T cells [58]. ROCK-mediated phosphorylation of the ezrin/radixin/moesin protein (ERM) leads to the enhancement of the CD44-ERM complex formation [58]. Our group and others have been reported a dysfunction of the ROCK-ERM-CD44 axis in T cells from SLE patients [59–61]. Pharmacological inhibition of ROCK in lupus-prone mice limited T-cells adhesion and migration leading to decreased the kidney pathology [62, 63]. In addition, ROCK2 was reported to facilitate the activity of interferon regulatory factor 4 (IRF4), which is required for the production of IL-17 and IL-21 [63]. Of note, PP2Ac in T cells is also involved in IL-17 production by promoting the ROCK-IRF4 pathway [64]. Collectively, the inhibition of ROCK could represent an important therapeutic regimen for the treatment of LN because it could limit entrance of T cells in to the kidney and the production of IL-17.

5.3. cAMP response element modulator (CREM)

CREM, which has multiple splicing variants encoding different isoforms, is an important component of cAMP-mediated signal transduction during cellular processes including T cell activation. Among isoforms of CREM, CREMα plays an important role in T cell differentiation and IL-17 production in SLE. Previous studies have revealed that T cells from patients with SLE have increased level of CREMα along with aberrant IL-17A expression [65]. Likewise, mice overexpressing CREMα in T cells display increased production of IL-17 and lupus-like disease [66]. Mechanistically, CREMα was found to bind to the IL17 promoter or IL17 locus to enhance its activity at the epigenetic level [65, 67]. In addition, CREMα is essential for the expansion of DN-T cells through epigenetic regulations of CD8a cells in patients with SLE and in lupus prone mice [68, 69]. Taken together, these observations indicate the potential of CREMα to serve as disease biomarker and possible therapeutic target in SLE because lowering its levels may suppress IL-17 production and shrink the pool of pathogenic DN-T cells.

5.4. Calcium/calmodulin-dependent protein kinase IV (CaMK4)

Calcium/calmodulin-dependent protein kinase IV (CaMK4) is a multifunctional serine/threonine kinase that regulates gene expression by activating transcription factors [70]. We have reported previously that CaMK4 is abnormally increased in T cells from patients with SLE [71] and lupus-prone mice [26]. In addition, we have also shown that CaMK4 expression is induced preferentially during Th17 differentiation and necessary for Th17 differentiation [72]. In line with these findings, genetic or pharmacologic inhibition of CaMK4 in MRL/lpr mice resulted in decreased the frequency of IL-17–producing T cells including CD4⁺ and DN T cells in spleens and in lymph nodes, a significant decrease of autoantibody production, improvement of nephritis and the survival rates [26, 73]. We have presented evidence using a Foxp3 reporter mouse in the MRL/lpr background that CaMK4 inhibition diminishes the accumulation of inflammatory cells followed by a reciprocal increase in Treg cells in the kidneys [74]. We recently demonstrate that CaMK4 facilitates anti-glomerular basement membrane antibody-induced glomerulonephritis in mice through the suppression of the CCR6/CCL20 axis at the inflamed sites [75]. Collectively, CaMK4-mediated aberrant T cell activity facilitates the development of LN via overproduction of IL-17 in lymphoid tissue as well as inflamed kidneys.

5.5 mammalian target of rapamycin complex 1 (mTORC1)

Mammalian target of rapamycin complex 1 (mTORC1) is a serine-threonine kinase that serves as a regulator of cellular metabolism and proliferation [76]. mTORC1 has recently emerged as an important regulator of Th1 and Th17 differentiation [77]. Importantly, CaMK4 [72] and ROCK [78] induce Th17 differentiation through mTORC1 pathway indicating the activation of mTORC1 contributes to Th17/Treg imbalance in autoimmune diseases including SLE. Moreover, recent studies have shown that the blockade by rapamycin reverses the expansion of Th17 cells in SLE patients [79, 80] and that rapamycin blocks glomerulonephritis in lupus prone mice [81]. Taken together, the inhibition of mTORC1 also has robust clinical benefits in patients with lupus nephritis.

6. Conclusion

SLE is an autoimmune disease with manifestations in multiple organs. Immune-system aberrations including lack of balance between Th17 and Treg cells, immune complexes, autoantibodies, inflammatory cytokines contribute to the expression of organ damage such as LN. In this article, we reviewed recent advances in molecular immunology of T cells and IL-17 and their clinical implications. We show the aberrant T cell signaling in the pathogenesis of LN in Figure 2. Biologic therapies and small-molecule drugs that target the aberrant T cell signaling and IL-17 production are desired for achievement of a favorable prognosis in patients with LN.

Figure 2.

The aberrant T cell signaling in the pathogenesis of LN. SLE: Systemic lupus erythematosus, TCR: T cell receptor, PP2Ac: Protein phosphatase 2A catalytic subunit, CaMK4: Calcium/calmodulin-dependent protein kinase IV, ROCK: Rho-associated protein kinase, CREB: cAMP response element binding protein, IRF4: interferon regulatory factor 4, CREM: cAMP response element modulator, mTORC1: mammalian target of rapamycin complex 1, Th: T helper, Treg: regulatory T cell.

Highlights.

• ▶Aberrant T cell signaling causes the development and progression of lupus nephritis.
• ▶IL-17 and Th17 cells play important roles in the pathogenesis of lupus nephritis.
• ▶PP2A, ROCK, CREM and CaMK4 facilitate IL-17 production in SLE.
• ▶T cell-targeted treatments are desired to achieve therapeutic goals in SLE.