Serum IL-17 levels are significantly associated with proteinuria (48, 49); and its concentration at the baseline keeps a positive correlation with the severity of proteinuria (50). In a study involving 15 patients (who underwent kidney biopsy), using the laser microdissection technique, the percentage of IL-17+ TCR+ among kidney-infiltrating cells correlated positively with hematuria in LN (51). In another study, elevated serum levels of IL-17 and IL-6 were associated with anemia (52).

Th17 cell frequencies significantly correlated with SLEDAI and inversely with C3 (53) and the concentration of IL-17 at the baseline kept a positive correlation with other parameters of severity (ESR, SLEDAI scores, and ANA titers) (50). In relation to histological activity, Th17 cell frequencies in peripheral blood and IL-17 levels in serum correlated significantly with renal biopsy classification for LN (43, 49, 53). A significant positive association has been found between serum IL-17 (and TWEAK) levels and nephritis activity index (54). In another study, the frequencies of circulating Th17-cells correlated positively with histological activity index, cellular crescent, and endocapillary proliferation. Additionally, intraglomerular levels of IL-17 and IL-23 were significantly higher in class IV LN than in MCN patients or HC (43). In another study, with measurement of urinary IL-17 (uIL-17), the levels of uIL-17 were significantly higher in the severe LN than in the control group (P < 0.05); and increased with disease severity seen in biopsy (mean ± SD: 43.96 ± 24.04, 55.69 ± 33.21, and 124.02 ± 256.74 pg/ml; for HC, class I-II, and class III-IV LN, respectively) (55). Another study observed that serum levels of IL-17A were significantly elevated in proliferative forms compared to non-proliferative LN (56).

A study found that the presence of IL-17 in renal tissue correlated with the requirement for pulse steroids (p < 0.05) (49). In relation to response to treatment, in a study involving 52 patients with active LN (who underwent kidney biopsy at baseline and after immunosuppressive therapy), higher IL-17 levels at baseline were associated with persisting active nephritis after treatment (WHO III, IV, V) (42). At follow-up, non-responders had higher IL-17 (and IL-23) expression by inflammatory cells infiltrating renal tissue than responders (42). On the other hand, IL-17 and IL-23 decreased significantly in patients with active LN after 6 months of therapy (P < 0.001) (45). Another study showed that despite a progressive decrease in serum concentrations of IL-17A and IL-21 during induction therapy, the concentration of these cytokines remained higher in the non-remission than in the remission group (50).

Th17 cell frequencies significantly correlated with serum creatinine (53) and IL-17 was an independent risk factor for poor prognosis of LN (48). In another study, IL-17 immunostaining in biopsy correlated negatively with GFR (49). Table 1 summarizes the clinical studies that have assessed the role of the Th17/IL-17 axis in lupus nephritis.

An early event in the classical immunopathogenesis of SLE is the easy release of intracellular content into the extracellular space, the breakdown of immune tolerance to self, and autoantibodies production (4, 67). Components released into extracellular space function as danger-associated molecular patterns (DAMPs) (4, 68) and are recognized by dendritic cells, and other antigen-presenting cells (APCs), through toll-like receptors (TLR4) present in their plasma membrane (69–72). On the other hand, autoreactive B cells respond to immunogenic DNA with autoantibodies production (67, 71, 73), which APCs also internalizes (through FCγRII) as DNA-containing immune complexes (68) and then recognized by TLR7 and TLR9 present in endosome (69, 74, 75). The binding of DAMPs to TLRs in APCs induces their maturation (76, 77). Mature APCs, in turn, drive lymphocyte activation (78).

Th17 cells differentiate from naive T auxiliary cells, according to microenvironmental factors, in the presence of IL-1β, IL-6, IL-23, and TGF-β, which are the key cytokines for its differentiation (78–80) and requires the lineage-specific transcription factor retinoid-related orphan receptor-gamma (RORγt) (80, 81). As described above, Mature APCs (after the binding of DAMPs to TLRs) trigger lymphocyte activation by the interaction of MHC II with TCR and several co-stimulatory molecules (15, 78, 80, 82). In the context of this interaction, mature APCs produce the key cytokines for Th17 differentiation (78, 80), using nuclear factor kappa B (NF-κB) and/or mitogen-activated protein kinase (MAPK) as signaling pathways (72, 77, 83). These cytokines bind to their respective receptors in naive CD4+ T Cells and trigger a chain of events downstream involving the Signal transducer and activator of transcription 3 (STAT3), which stimulates the synthesis of IL-17 and IL-21 either by binding directly to their genes or by activating RORγt (80, 84). Interestingly, T cells from SLE patients presented enhanced Stat3 activity added to higher RORγt expression (85). Once differentiated, Th17 cells secrete their cytokines (IL-17A, IL-17F, IL-17C, IL-21, and IL-22), most of them with a pathogenic role in the kidney (32, 86–88), in addition to its systemic effects (1, 15).

Regarding Th17 cells differentiation, it is also worth mentioning that podocytes, mesangial cells, and renal tubular epithelial cells can behave as antigen-presenting cells (89–92). So, these intrinsic renal cells can alone trigger the local activation of Th17 cells after recognizing, processing, presenting eventual DAMPs that cross the glomerular filtration barrier, as seen in other kidney disease models (89, 93, 94). Interestingly, a study showed that IL-17 (and IFNγ) upregulated the expression of MHC-I, MHC-II, and co-stimulatory molecules (CD80 and CD86) on the podocyte surface. Moreover, under IL-17 stimulation, podocytes increased the uptake and processing of antigen, resulting in the presentation of its peptide on the cell surface (93). This fact brings robustness to the idea that, in part, naïve T cells can enter the kidney and continue, under local factors, in the path of differentiation and activation to Th17 (95, 96). A recent study reinforces this thesis by demonstrating that, in kidneys of patients with ANCA-associated glomerulonephritis, Th17 cells develop from CD4+ tissue-resident memory T cells and exacerbate renal pathology by secreting IL-17A (97, 98).

Although the same general mechanisms regulate the activation of all T-cell subtypes (effector and regulatory) it is worth emphasizing that in the lupus autoimmunity environment, there is favoritism of self-reactive effector (4, 73, 99); with the detriment of regulatory cells (17, 97, 100). One of the bases of this polarization lies in the fact that there are plasticity and reciprocity between Th17 and Treg (100–102), a balance influenced by various factors (103), and the inflammatory and autoimmunity environment of lupus favors to the side of the Th17 cells (2, 79, 101). Added to Th17/IL-17 axis overactivity, LN is characterized by decrease, suppression, or dysfunction of Treg cells (57, 104) and impairment of other protective factors like IL-2 (97) and IL-10 (105, 106).

Several aspects present in SLE favor the polarization of CD4+ cells to a proinflammatory profile (Th1 and Th17) (2, 107). This range from phenotypic and functional aberrations of APCs (2, 108, 109) to T cells specific aspects, like changes in immunometabolism (marked glycolysis, lipid synthesis, glutaminolysis, and hyperactivation of the mTOR pathway) (110, 111), and abnormalities in signaling pathways (112, 113). In addition, epigenetic changes, such as histone hypomethylation at naive CD4+ T Cells level, have also been described to favor Th17 polarization (114, 115) and were early events before lupus flares (114). Additionally, dysbiosis, a characteristic also present in lupus (116, 117), is a potentiating factor for Th17/IL-17 polarization (118); and a study has even shown that autoimmune kidney disease is exacerbated by the migration of pathogenic Th17 cells from the intestine to the kidney (119).

In the lupus autoimmunity environment, other elements of the immune response participate in Th17 polarization, as shown in an experimental study with lupus-prone mice, in which dendritic and B cells increased Th17 expansion, associated with limited Treg expansion, and increased renal infiltration by Th1 and Th17 cells (2). In another study, basophils obtained from patients with SLE promoted Th17 differentiation from SLE naïve CD4+ T cells in vitro coculture (120). Even cells with a dominant protective role, like Treg cells, in the lupus nephritis background, have been shown to facilitate the proliferation of Th17 lymphocytes and are less suppressive (47, 63). Several other elements of the immune response favor polarization to Th17 in the context of lupus (121).

Th17 cells are attracted to the kidney by chemokines CCL20, CXCL9, and CXCL10 (33, 122, 123) through binding to their receptors (CXCR3 and CCR6) expressed on the surface of these cells (124–126). Recruitment is facilitated by the enhanced migratory capacity of Th17 cells from SLE patients, through high Akt activity (60) and involvement of calcium/calmodulin-dependent kinase IV (CaMK4) (96, 127). Most intrinsic kidney cells (podocytes, mesangial, and kidney tubular cells) secrete CXCL9, CXCL10, and CCL20 in response to injury (23, 123, 128). In an experimental study, stimulation of mesangial cells with nucleosome-containing immune complexes resulted in their activation and expression of CCL20 (129). More recently, it has been shown that components of the extracellular matrix, produced by injured cells, stimulate resident macrophages to produce CCL20, CXCL9, and CXCL10, cooperating in this way in the recruitment of Th17 cells (130).

Once in the kidney, Th17 cells maintain the phenotypic and functional features through several other factors, as demonstrated in models where local T cells had elevated expression of inducible T cell costimulator (ICOS) coreceptor and were protected from apoptosis by elevating the activity of the PI3K-Akt signaling pathway. These features together result in facilitating the accumulation of active T cells in the kidney (131, 132). Additionally, a clinical study revealed that LES patients had elevated serum autoantibodies against co-inhibitory PD-1, facilitating T cell proliferation and maintaining the hyperactive phenotype; and this kept a close association with disease activity, particularly renal involvement (133).

In the kidney, the Th17/IL-17 axis participates in several points of the damage chain. In summary, this involves changes in the structure and functioning of intrinsic specialized renal cells, promoting and maintaining an inflammatory environment, participating in repetitive tissue damage and maladaptive repair, leading to renal fibrosis and loss of function (23, 25). Thus, the Th17/IL-17 axis behaves as a true chief orchestrator of immunity (134, 135). The available evidence on the Th17/IL-17 axis effects on specific renal cells or compartments is described below in this review.

The Th17/IL-17 axis role as a mediator of kidney damage and fibrosis has been found in various other renal diseases (in both patients and animal models) (198–200). These include primary glomerular diseases (198, 201), diabetic nephropathy (199, 202, 203), hypertensive nephropathy (175) ischemia-reperfusion models (37, 87, 200), renin-angiotensin-aldosterone system-mediated damage (204, 205), unilateral ureteral obstruction associated damage (36, 95, 206), and in ablation or unilateral nephrectomy associated damage (207).

Th17/IL-17 axis seems to increase the risk of CKD itself, as seen in a genetic study with 650 elderly, where single nucleotide polymorphism (SNP) of IL17RA (rs4819554 AA homozygotes) was significantly more frequent among individuals with eGFR < 60 ml/min/1.73 m²; and was associated to the risk of developing ESRD (40). Another study including 290 non-diabetic ESRD patients and 289 normal controls found that patients had a significantly higher frequency of IL17E rs10137082^*C and IL17RA rs4819554^*A alleles compared to control. At the same time, the genotyping analysis found that SNPs for IL17E (rs10137082) and IL17RA (rs4819554) were significantly more frequent among patients than in controls, after adjusting for confounders (208). It is important to highlight that this is an association and not necessarily a causal relationship because SNPs are hardly a causal factor alone. This is even less likely in a disease like lupus, with heterogeneous and multifactorial etiology (5, 209). However, associated SNPs may be players with additive or synergistic effects at the confluence of the multi-players that characterize the disease (11, 111).

Additional evidence about the role of the Th17/IL-17 axis on Kidney diseases comes from the observation of the increased risk of CKD associated with renal inflammation in human diseases that occur with the hyperactivation of the Th17/IL-17 axis, like psoriasis (210–212), rheumatoid arthritis (213, 214), and ankylosing spondylitis (215–217). In two studies (in the United Kingdom and Taiwan), psoriasis was associated with an increased risk of chronic kidney disease independent of traditional risk factors (211, 212). The myriad of exposed situations suggests that Th17/IL-17 is a permanent participant, or at least as a pivotal element, in the pathogenesis of many kidney diseases independent of the initial insult (218); and its role extends from initial mechanisms, ESRD, to consequences of CKD and dialysis (88, 205, 207, 219).

The role of the Th17/IL-17 axis has been found in other organic diseases that combine both inflammatory and fibrosing courses (219–221). Thus, the axis is involved in intestinal fibrosis in inflammatory bowel disease (222, 223), in pulmonary fibrosis in systemic sclerosis and cystic fibrosis (220, 224), liver cirrhosis (221, 225) and peritoneal fibrosis (219, 226). Its blockage and/or suppression has emerged as promising to prevent/mitigate the inflammatory and/or fibrosing behaviors in such conditions (226–228). Figure 2 summarizes the Th17/IL-17 axis effects on intrinsic renal cells and immune cells with potential implications in kidney damage, particularly in lupus nephritis.

The Th17/IL-17 axis participates in the production of autoantibodies by B cells, as demonstrated in studies with autoimmune models in which the IL-17 drives the development of autoreactive germinal center (GC); and mice lacking the IL-17 receptor have reduced B cell development and humoral responses (229, 230). In another study with an autoimmune disease model, the blockade of IL-17 signaling was associated with a significant reduction in both the number and size of germinal centers (231).

The IL-17RA receptor is essential for the optimal location of follicular helper T cells (Tfh) in the light zone (LZ) of the GC to promote the production of autoantibodies by B cells (195). Additionally, the production of IL-17 initially correlates with a reduced migratory response of B cells to chemotactic like CXCL12, suggesting that IL-17 not only facilitates the interaction between Tfh and responder B cells but also prolongs this interaction by increasing the time of permanence of B cells in GC (229).

In relation to the structure and functioning of the germinal center, a lymph node study showed that IL-17 is a critical requirement for the proliferation of lymph node and splenic stromal cells, particularly fibroblastic reticular cells (FRCs), during experimental autoimmunity. Without IL-17 signaling, there was a failure in FRC proliferation (nutrient stress, arrested cell cycle, and apoptosis), resulting in the impaired germinal center formation and antigen-specific antibody production (196).

The IL-17 importance in the production of autoantibodies was also evidenced in another study in which the PBMC supernatants from LN patients expressed higher levels of IgG, anti-dsDNA under IL-17 stimulation than in a normal culture medium. This effect occurred in a dose-dependent manner, and could be blocked completely by IL-17 monoclonal antibodies or partially by dexamethasone (58). Another experimental study showed that IL-17 increased anti-double-stranded DNA antibody production, and this was the link in the correlation between cytokine levels and disease severity (185). A recent study has ratified the crucial role of IL-17 by demonstrating that IL-17 promotes autoantibody production and increases plasma cell survival. In this study, the subset of plasmocytes expressing the IL-17RC receptor had an exponential increase in the production of anti-dsDNA IgG upon IL-17A stimulation in both patients and mice. Additionally, the transfer of Th17 depleted PBMC resulted in a significant reduction of autoantibody production and attenuation of renal damage. This attenuating effect was also observed in IL-17 or IL-17RC deficient mice, while the adoptive transfer of Th17 to IL-17-deficient mice restored the plasma cell response and renal lupus damage. The most important is that IL-17 significantly promoted plasma cell survival, through phosphorylation of p38, stabilizing Bcl2l1 mRNA, which encodes the anti-apoptotic protein Bcl-xL (197).

Amplification of the inflammatory response is among the systemic effects of IL-17. This includes granulopoiesis and myelopoiesis by stimulating the synthesis of GM-CSF and G-CSF, increased production of chemokines, and inflammatory cytokines (31, 192); in addition to associated paralysis or impairment of anti-inflammatory pathways (105). In these effects, IL-17 makes synergy with several other inflammatory mediators such as IFN-γ, TNF-α, and IL-23 (42, 49, 232, 233). In a PBMC culture medium, stimulation with IL-17 induced significant IL-6 mRNA transcription in PBMC from LN patients than from HC (58). This study also brings the notion that, compared to controls, cells from lupus patients are hyperresponsive with higher production of inflammatory mediators under the same stimulus conditions (58).

In neutrophil kinetics, especially, IL-17 participates in various points of the chain, from differentiation through the synthesis of colony-stimulating factors (31); recruitment of neutrophils to the target organs through endothelial cell activation in a STAT3 and/or MAPK-dependent manner (34, 234) and by the synthesis of attracting chemokines like CXCL5, CXCL1; and CXCL8/IL-8 (86, 235). In relation to CXCL1, a potent chemoattractant for neutrophils, it is worth mentioning that IL-17 participates in regulating its production and in the stability of its mRNA (232, 235) and increases its biological half-life (236).

The Th17/IL-17 axis seems to have a cooperative relationship with other pathways whose importance is highlighted in the pathogenesis of SLE, like Type I interferons (6, 11, 237). This was evidenced by studies that found increased IL-17A and IL-17A-producing cells in IFN+ than in IFN- patients and HCs (238, 239). In one of these studies involving 31 patients with SLE, patients displaying high IFN-α bioactivity (58.1% of them) had a higher frequency of Th17 cells in peripheral blood than those with low IFN-α bioactivity (mean ± SD 1.9 ± 1.0 vs. 1.2 ± 0.9). Additionally, subjects with high IFN-α bioactivity and elevated Th17 cells had significantly higher disease activity and serum IL-6 levels than those with low IFN-α and Th17 cells. Suggesting that IFN-α and Th17 cell pathways co-exist and co-regulate the disease pathogenesis (238). Other studies found a significant correlation between the Th17/IL-17 axis and B-lymphocyte stimulator (BLyS/BAFF), a factor strongly correlated with IFN type I (239, 240). In another study involving 33 patients with cutaneous lupus erythematosus who underwent biopsy, the level of IL-17A in tissue correlated positively with the IFN-α expression (Spearman's ρ = 0.56) (20).

The repercussion of this relationship between Type I IFN and the Th17/IL-17 axis in kidney damage was evident in an experimental model in which mice deficient in IL-17RA were protected from Type I Interferon-dependent crescentic glomerulonephritis. This effect was associated with impaired renal infiltration by activated macrophages, despite unaffected systemic response (147). As the underlying mechanism, the authors have shown that IL-17 in association with IFN-I differentially regulates the expression of macrophage chemoattractants genes, including Ccl2 (encoding CCL2) in RTEC (147). However, no primary study evaluated this relationship in LN in humans. A gap in knowledge to be filled in next studies, and combining genetic studies with integrative Bayesian network approaches may bring additional information to current knowledge in this disease characterized by heterogeneity (209).

The Th17/IL-17 axis may be the bridge (or part of it) between LES and other organs comorbidities and outcomes (241, 242), such as cardiovascular disease because it is known to promote endothelial activation (233, 234), prothrombotic states (167, 168), hypertension (166, 177), and atherogenesis (207, 243, 244); and osteoporosis because it is known to increase bone catabolic activity (245).

Several agents directly interfere with the axis and are approved to treat diseases in which the Th17/IL-17 axis clearly drives the inflammation. So, secukinumab and ixekizumab are agents targeting IL17A, both approved for ankylosing spondylitis, plaque psoriasis, and psoriatic arthritis (246); Bimekizumab that neutralizes both IL-17A and IL-17F is in preclinical phases for psoriatic arthritis and ankylosing spondylitis (247) and brodalumab an anti-IL17R, is approved for plaque psoriasis (248). Regarding the use of these agents in lupus, there are no studies completed so far; however, there are two ongoing trials to assess the safety, efficacy, and tolerability of secukinumab in patients with active lupus nephritis (NCT04181762); and the safety and efficacy of secukinumab in cutaneous manifestation of lupus (NCT03866317). In a case report involving a patient with lupus nephritis complicated by psoriasis vulgaris, the use of secukinumab was reported to be effective for both conditions with improvement in clinical and laboratory parameters (249).

The Th17/IL-17 axis can be targeted indirectly in several ways, from interfering in the differentiating pathways, inhibition of migratory capacity, acting on mechanisms that favor polarization, including immunometabolism.

The differentiating pathways of Th17 cells are also a therapeutic target to be explored to prevent the prosperity of the axis. In fact, in a clinical trial, the addition of ustekinumab, a human monoclonal antibody against IL-12 and IL-23, to standard care resulted in better efficacy in clinical and laboratory parameters (250). It is noteworthy that il-23 not only drives the expansion, survival of pathogenic Th17 and other IL-17-producing cells (84) but also decreases Treg by decreasing the production of IL-2 (the positive regulator of Treg) (251). Thus, the beneficial effect of its inhibition should involve as mechanisms the decrease of Th17 and the increase of Treg, the impairement of the IL-23/IL-17 synergisms, among other potential mechanisms. Still, on the path of differentiation, the inhibition of STAT3, the main Signal transducer in Th17 differentiation, delayed/limited the installation of lupus nephritis in experimental models (252–254). In another experimental model of LN, renal pathological damage was attenuated with the use of α-mangostin and 3β-acetyloxy-oleanolic, compounds with inhibitory activity on retinoic acid receptor-related orphan receptor gamma t (RORγt), the transcription factor for Th17 differentiation. These compounds significantly decreased serum anti-dsDNA antibody levels, IL-17A, and IFN-γ expression (255, 256).

Since metabolic changes at the level of T cells are important in Th17 polarization and immune hyperreactivity, targeting the immunometabolism is another potentially promissory indirect strategy in SLE (110, 111). In experimental studies, metformin, which inhibits oxygen consumption and glucose oxidation, inhibited the activation of T cells, with a consequent decrease in the production of IFN-γ and IL-17 (257, 258). In another study with glucose transport inhibitors (CG-5), there was a decrease in Th1 and Th17 polarization by inhibiting their differentiation, accompanied by induction of regulatory T (Treg) (259). In addition to the effect on T cells, CG-5 treatment reduced the expansion of B cells in GC and autoantibodies' production (259). However, in a clinical trial, the addition of metformin to standard care could not demonstrate an additional benefit in reducing SLE recurrence (260). The hyperactivation of the mTOR pathway, a feature that favors Th17 polarization, is another potential target. In two studies with SLE patients, the use of rapamycin (an inhibitor of mTOR pathway) in combination with IL-2 or all-trans retinoic acid (ATRA) showed clinical efficacy decreasing the disease activity, associated with reduced Th17 cells, and restoration and long-term maintenance of Treg/Th17 ratio balance (261, 262). Aligned with this data, in a 12-months prospective open-label study, rapamycin significantly reduced the disease activity scores (SLEDAI and BILAG), associated with a reduction in IL-17 production (either by Th17 cells or double-negative T cells) (263). A trial is registered to assess the efficacy and safety of rapamycin in patients with active SLE (NCT04582136).

Several other agents have shown their potential in improving SLE interfering with the axis. Thus, the immunomodulatory efficacy of stem cell therapies (either Umbilical cord, Bone Marrow or adipose-derived) involves the suppression of the axis or restoration of the Treg/Th17 balance (12, 154); and defects in the functioning of stem cells trigger the disease (121). The beneficial effect of specific MicroRNA as miR-125a-3p and MicroRNA-10a-3p also involve interference on the axis (153, 264). In an experimental study, punicalagin (a bioactive antagonist of PAR2) ameliorated lupus nephritis, in association with a significant reduction in splenic Th17 populations compared to the vehicle controls (265). Remembering that PARs are involved in Th17-induced rearrangement in the cytoskeleton and increased permeability (136). In an experimental study with MRL/lpr mice, a traditional Chinese medicinal formula suppressed the IL-17 production and Th17 activity by inhibiting the expression of CaMK4, which was associated with a decrease in renal hypercellularity and infiltration by neutrophils (266). It is worth remembering that CaMK4 is involved in Th17 activity and enhances its migratory capacity (96).

Many of the drugs with just known efficacy in the treatment of lupus, and which act on other biological targets, have a parallel effect on the Th17/IL-17 axis. Thus, for example, the effect of methylprednisolone on improving lupus nephritis was also associated with the rebalancing of Splenic CD4+ cells with a significant reduction in Th17 populations compared to controls in an experimental study (265). This corroborates the clinical observation that induction treatment was associated with the progressive reduction of IL-17A, IL-6, and IL-21 (50). Hydroxychloroquine, an immunomodulator in lupus, inhibited Th17 differentiation (267), and reduced Th17-related cytokines in patients (268). Mycophenolic acid, used in an experimental study, inhibited the production of IL-17A, which occurred with the reduction of granulopoiesis; and this effect was completely abolished in mice lacking the IL-17 receptor (269). The same drug showed an effect of reducing STAT3 phosphorylation in patients with SLE (270), which is crucial in synthesizing IL-17 and IL-21 (84). Even Belimumab, a recombinant human IgG-1λ monoclonal antibody that inhibits B-cell activating factor (BLyS/BAFF), effective in lupus nephritis (271), shown to occur, in its effectiveness, with the restoration of the Treg/Th17 balance (272).