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IL-17 in Renal Immunity and Autoimmunity Partha S. Biswas J Immunol 2018; 201:3153-3159; ; This information is current as doi: 10.4049/jimmunol.1801042 of September 25, 2021. http://www.jimmunol.org/content/201/11/3153 Downloaded from References This article cites 86 articles, 27 of which you can access for free at: http://www.jimmunol.org/content/201/11/3153.full#ref-list-1

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. IL-17 in Renal Immunity and Autoimmunity Partha S. Biswas The kidney is an organ particularly susceptible to role in acute or chronic kidney diseases. The objective of this damage caused by infections and autoimmune condi- review is to outline some of the evidence connecting immune tions. Renal inflammation confers protection against and inflammatory mechanisms in renal antimicrobial im- microbial infections. However, if unchecked, unre- munity and autoimmune kidney diseases (Fig. 1). solved inflammation may lead to kidney damage. In the past decade, IL-17A (IL-17), a proinflammatory Although proinflammatory IL-17 is required cytokine, has received considerable attention for its pathogenic for immunity against extracellular pathogens, dysregu- role in autoimmune diseases. Although protective in infectious lated IL-17 response is also linked to autoimmunity. settings, overproduction of IL-17 promotes inflammation and autoimmunity (4). IL-17 recruits and stimulates different cells

In this review, we will discuss the current knowledge Downloaded from of IL-17 activity in the kidney in context to renal im- to drive chronic inflammation. Regulating IL-17 levels or munity and autoimmunity and raise the intriguing action by using IL-17 or IL-17R blocking Abs has shown remarkable efficacy in attenuating experimental autoimmune question to what extent neutralization of IL-17 is ben- diseases. In this review, we will overview IL-17 induction and eficial or harmful to renal inflammation. The Journal function in relation to host defense and autoimmune diseases of Immunology, 2018, 201: 3153–3159. in the kidney. http://www.jimmunol.org/ Biology of IL-17 he kidneys are frequent targets of infectious agents as IL-17 (IL-17A, also termed CTLA-8) was originally cloned in well as pathogenic immune response in systemic and 1993 (5). The IL-17 family consists of six : IL-17A T organ-specific autoimmunity. According to the Na- (IL-17), IL-17B, IL-17C, IL-17D, IL-17E (IL-25), and tional Institutes of Health, ∼14% of the people (∼20 million) IL-17F (6, 7). The IL-17R family includes five receptor in the United States suffer from some form of chronic kidney subunits, IL-17RA, IL-17RB, IL-17RC, IL-17RD, and diseases (https://www.niddk.nih.gov/). In addition, pyelone- IL-17RE (7). IL-17 and IL-17F exist either as a homodimer phritis is a frequent complication of urinary tract infection or as a heterodimer and signal through dimeric IL-17RA and by guest on September 25, 2021 (UTI) by Escherichia coli, the most frequent infection in hu- IL-17RC receptor complex (7). Although IL-17R is ubiqui- mans (1). Yet our understanding of the fundamental immune tously expressed, nonhematopoietic cells are generally the processes in the kidney lags behind that of other visceral or- principal responders to IL-17. Upon ligand binding, adaptor gans, such as the gut or liver. The kidney is an immunolog- Act1 is recruited to the receptor subunits and activates ically distinct organ, owing to its poor regenerative capacity, multiple pathways via different TNF receptor– toxins (uremia), hypoxia, and arterial blood pressure, which associated factor (TRAF) . Activation of TRAF6 leads have profound impacts on the ongoing immune response in to triggering of multiple factors, including the kidney (2, 3). Additionally, lack of reliable animal models NF-kB, C/EBPb, C/EBPd, and MAPK (7). IL-17R–Act1 of kidney diseases and technical difficulties in procuring complex also links with MEKK3 and MEK5 in a TRAF4- adequate human renal biopsy samples make it challenging dependent manner, resulting in ERK5 activation (7). Al- to interrogate pathways linked to host defense and autoim- though TRAF6 and TRAF4-mediated IL-17 signaling results mune diseases in the kidney. Conversely, kidney failure dis- in transcription of classical IL-17 responsive inflammatory turbs immunity, causes intestinal barrier dysfunction and , IL-17 signaling via Act1-TRAF2-TRAF5 complex dysbiosis, and drives systemic inflammation or immunodefi- controls mRNA stability of IL-17 target genes. ciency. Therefore, kidney disease is a major health problem, IL-17 induces inflammatory expression either by and understanding the mechanisms leading to renal disease is driving de novo gene transcription or by stabilizing target an important endeavor with a great potential health impact. mRNA transcripts. IL-17 activates NF-kB and induces the Renal inflammation and immune system activation play a key expression of NF-kB–dependent cytokines. Subsequent studies

Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, Abbreviations used in this article: ANCA, antineutrophilic cytoplasmic Ab; KKS, PA 15261 kallikrein–kinin system; MMP, matrix metalloproteinase; MRSA, methicillin-resistant Staphylococcus aureus; TRAF, TNF receptor–associated factor; UPEC, uropathogenic Received for publication July 27, 2018. Accepted for publication August 7, 2018. E. coli; UTI, urinary tract infection. This work was supported by the Division of Rheumatology and Clinical Immunology, University of Pittsburgh Medical Center, and the National Institutes of Health (Grant Copyright Ó 2018 by The American Association of Immunologists, Inc. 0022-1767/18/$37.50 DK104680 to P.S.B.). Address correspondence and reprint requests to Dr. Partha S. Biswas, S725 Biological South Tower, Division of Rheumatology and Clinical Immunology, University of Pitts- burgh, 3500 Terrace Avenue, Pittsburgh, PA 15261. E-mail address: [email protected] www.jimmunol.org/cgi/doi/10.4049/jimmunol.1801042 3154 BRIEF REVIEWS: IL-17 ACTIVITIES IN THE KIDNEY

response is initiated by several classes of pattern recognition receptors, such as membrane-bound TLRs and nucleotide- binding oligomerization domain (NOD)–like receptors, to- gether with inflammasomes. Following pathogen clearance, both innate effector cells and kidney-resident cells release tissue repair enzymes and anti-inflammatory proteins, which are necessary to maintain immune homeostasis and repair injured tissue. Innate response also set the stage for adaptive immunity, required for long-term protective immunity in the kidney. IL-17–mediated renal immunity against bacterial infections. The most common bacteria responsible for kidney infection is E. coli, which accounts for close to 80% of cases of kidney (pyelone- phritis), urinary tract, and bladder infections (cystitis) (23). Other bacteria include methicillin-resistant Staphylococcus aureus (MRSA), Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa,andEnterococcus faecalis (23). Uropathogenic E. coli. UTI caused by uropathogenic E. coli Downloaded from (UPEC) is one of the most common infection in humans, affecting 150 million people each year worldwide (23). FIGURE 1. Renal activities of IL-17 in kidney diseases. Kidney is subject to Bacteria present in fecal matter infect the peri-urethral area many infections as well as autoimmune injury. IL-17 is detected in the kidney following renal infections and autoimmune conditions. Owing to its proin- and bladder. If left unchecked, the bacteria ascend the ureters flammatory properties, IL-17 is critical to host antimicrobial defense. However, to the kidney and establish acute pyelonephritis. In most http://www.jimmunol.org/ if unrestrained, IL-17 signaling is linked to many autoimmune kidney diseases. severe cases, UPEC infection may lead to permanent renal scarring and septicemia (1). Sivick et al. (24) systematically interrogated the impact of identified a characteristic “IL-17 gene signature,” including IL-17 in innate and adaptive immunity against UPEC in a cytokines (IL-6, IL-1, G-CSF, GM-CSF and TNF-a), che- mouse model of trans-urethral infection. In this system, IL-17 mokines (CXCL1, CXCL2, CXCL5, CCL2, CCL7 and has been shown to play no role in adaptive immune response CCL20), (b-defensins, S100 proteins, in the bladder. In contrast, IL-17 produced by gd+ T cells and lipocalin2), and matrix metalloproteinases (MMPs) drives bacterial clearance in the infected bladder at an early

(MMPs 1, 3, 9, and 13) (8, 9). Moreover, tissue-specific gene by guest on September 25, 2021 time point. The protective effect of IL-17 was attributed to its targets are also identified in different organs. For exam- ability to induce cytokines and necessary to fa- ple, IL-17 upregulates renal-protective genes encoding the cilitate the influx of neutrophils and other innate effectors in kallikrein–kinin system (KKS) in Candida albicans–infected kidney, which prevent kidney damage during acute or chronic the bladder. In line with this observation, mice deficient in gd+ kidney injury (10, 11). IL-17 also activates MAPK pathways, T cells showed increased susceptibility to UTI (25). including ERK, p38, and JNK (12). Additionally, C/EBP However, this study did not measure renal IL-17 levels or transcription factors act as transcriptional regulators of IL-17 investigate the contribution of IL-17 in defense against UPEC signaling in target cells (13). in the kidneys. A separate report showed that expression of IL-17 came into prominence in 2005 with the discovery of a IL-17 is increased in the kidney following UPEC infection at new population of CD4+ Th cells characterized by the ex- 24 and 48 h postinfection. This increase in IL-17 level is pression of IL-17 (14–17). This subset became known as regulated by surfactant proteins A and D in the infected Th17 cells. During priming of naive CD4+ T cells, APCs kidney (26). Consequently, surfactant proteins A and D secrete IL-1, IL-6, and IL-23. This favors Th17 differentiation knockout mice showed increased bacterial load in the kidney via STAT3 and RORgt and secretion of IL-17, IL-17F, following UPEC infection. Future in-depth studies should GM-CSF, and IL-22. Furthermore, a number of innate im- focus on addressing the renal activities of IL-17 in the kidneys mune subsets make IL-17, such as gd+ T cells, NK T cells, following UTI infection. and TCRb+ natural Th17 cells and type 3 innate lymphoid MRSA. MRSA infection is a major clinical challenge and in most cells (ILC3) (18). cases is difficult to treat. Although MRSA resides in the skin and nasal tract, infection of kidney may occur through blood stream Renal immunity against pathogens infection and from ascending spread from urinary tract (27). If Kidneys in a healthy state are sterile. However, renal infections uncontrolled, MRSA infection in the kidney may lead to the are common and occur via hematogenous routes or from development of more serious conditions, including septic ascending spread from the bladder or urethra. The very early shock. The first evidence documenting a 15-fold increase in the response to invading pathogens is provided by the unidirec- kidney burden of MRSA following IL-17 neutralization tional flow and acidic pH of urine and epithelial barriers and suggests that IL-17 plays a vital role in protecting against local production of antimicrobial factors that trap pathogens or disseminated infection (22). Interestingly, neutralization of interfere with their ability to attach to tissue (2, 19–22). This is IL-22, another cytokine produced by Th17 cells, has no followed by a robust innate immune response in the kidney, impact on renal bacterial load. Kidneys of mice subjected to which provides the first line of host defense. The innate IL-17 neutralization showed reduced number of T cells and The Journal of Immunology 3155 neutrophils. However, renal expression of antimicrobial IL-17 is classically known as a regulator of neutrophils and peptides and cytokines were unchanged (28). Indeed, protective antimicrobial peptides. Neutrophil influx was reduced in the 2 2 efficacy of NDV3 vaccine against invasive MRSA infection kidneys of IL-17RA / mice during disseminated candidiasis requires the induction of IL-17 response (29). O-Acetylation of (39). Furthermore, mobilization of the neutrophils in the peptidoglycan of MRSA limits Th17 cell priming and permits blood during systemic challenge with C. albicans was also MRSA reinfection in the absence of functional Th17 memory impaired. Interestingly, two reports indicated that IL-17– (30). Moreover, vaccination with recombinant N terminus of the driven signaling in disseminated candidiasis does not occur in candidal Als3p adhesin resulted in ∼5-foldreductioninkidney the kidney but instead targets bone marrow to stimulate NK bacterial burden and improved survival in mice. The vaccination cell production of GM-CSF: a cytokine responsible for primed Th1, Th17, and Th1/Th17 cells in the draining lymph driving candidacidal activity of neutrophils in the kidney nodes,whichinturnstimulatedneutrophilinfluxand (41, 45). In sharp contrast, we showed that IL-17R expression proinflammatory cytokine levels in the kidney (31). A new on nonhematopoietic cells is required for host defense against report showed that vaccination with nontoxic mutant TSST-1 disseminated candidiasis, and there is no contribution for drives IL-17–dependent protection against S. aureus infection hematopoietic cells (44). IL-17 acts on renal tubular epithelial (32). In vaccinated animals, IL-17 producing cells were cells to induce the expression of nephron-protective KKS increased in the spleen and the vaccine-induced protection (10). Activation of KKS is critical to prevent kidney damage against S. aureus was abolished in the IL-17 knockout mice (32). and restore renal function by inhibiting apoptotic cell death of kidney-resident cells during hyphal invasion. Accordingly, Downloaded from IL-17–mediated renal immunity against fungal infections. Invasive treatment of mice with specific KKS agonist, currently in fungal infections are a major cause of mortality in hospitalized clinical trial for numerous inflammatory diseases (https:// patients (33). The opportunistic pathogens such as Candida, www.clinicaltrials.gov), prevents renal damage and improved Aspergillus, Mucor, Cryptococcus, and Histoplasma are partic- survival following disseminated candidiasis (10, 44). Inter- ularly known to infect the kidneys in predisposed individuals estingly, vaccination with candidal Als3p adhesin with alu- with serious complications. At the same time, there is a high minum hydroxide adjuvant lowers renal fungal burden by a http://www.jimmunol.org/ incidence of invasive fungal infections in patients with renal log in a Th17 and neutrophil-dependent manner (31). In disease and kidney transplant recipients under effects of im- contrast, mice deficient in IL-17C show improved survival munosuppression and environmental exposure (34). There due to reduced renal inflammation and damage in the fungal are two mechanisms by which these fungal species infect the infected kidney (46). Supporting this line, others have pro- kidney; infections can begin in the lower urinary tract and posed that the Th17-induced activation of neutrophils may ascend to the kidneys, and infection can also occur via he- also result in an overwhelming inflammatory tissue response matogenous dissemination to the kidneys. that impairs antifungal immune resistance and leads to de- C. albicans is the causative agent of candidiasis at the mu-

fective pathogen clearance (47). Although renal infections by by guest on September 25, 2021 cosal sites, including oral cavity, skin, and vagina (35). non–C. albicans species are increasing at an alarming rate, However, the most severe Candida-induced disease resulting ∼ very little is known about the role of IL-17–dependent renal in high mortality rate ( 40%) is disseminated candidiasis (33, immunity against these fungal species. A recent analysis of 36, 37). The kidney is the most common organ involved in C. tropicalis systemic infection in mice revealed that IL-17R/ disseminated candidiasis. This was demonstrated in a review Act1 signaling is dispensable for antifungal immunity, of 45 autopsies of patients with disseminated candidiasis. whereas CARD9 and TNF-a signaling in neutrophils are Almost 89% (40 out 45) had overt histological evidence of essential (48). renal involvement (38). Similarly, the majority of the fungus is recovered from the kidneys of systemically infected mice. IL-17 in autoimmune kidney diseases During disseminated candidiasis, C. albicans hyphae invade IL-17 is a pleiotropic cytokine that plays important role in and damage kidney leading to renal insufficiency (10). Con- tissue inflammation. This is primarily mediated by inducing siderable data implicate IL-17 in immunity to disseminated the expression of proinflammatory cytokines, chemokines, and candidiasis (39–42). Data from our group and others have MMPs. As kidney is often affected by dysregulated systemic or shown that IL-17 is produced locally in the kidney within 24 organ-specific immunity, in this article, we will only highlight to 48 h in response to fungal infection (10, 43). Accordingly, the pathogenic role for IL-17 in autoimmune kidney diseases. mice lacking IL-17RA or IL-17 exhibited increased fungal Mouse models of experimental autoimmune glomerulonephritis. load in the kidney and succumb to infection earlier than Since the discovery of Th17 cells in 2005, IL-17 has been control animals (39–42). implicated in many autoinflammatory diseases. Interestingly, Although IL-17 has been detected in the fungal infected the link between IL-17 and renal inflammation was first kidney, the exact cellular source of IL-17 was unknown. By demonstrated long before the discovery of Th17 cells. Van taking advantage of sensitive IL-17 fate tracking mice, we Kooten et al. (49) showed that IL-17 drives the expression + demonstrated that innate gd T cells are the primary cellular of cytokines and chemokines from tubular epithelial cells source of IL-17 in the C. albicans–infected kidneys, with under in vitro condition. We demonstrated that IL-17– + minor contribution from innate ab T cells (44). In unin- mediated expression of inflammatory mediators’ from tubular fected mice, a small baseline population of IL-17–producing epithelial cells is critical for migration of neutrophils. Similarly, gd+ T cells was also observed, which proliferated in response mice deficient in IL-17R signaling showed diminished to systemic fungal infection. These data indicate that both neutrophil influx, but not and , in a kidney resident and infiltrating gd+ T cells may contribute to mouse model of anti–glomerular basement membrane renal IL-17 production in the fungal infected kidney. glomerulonephritis (50). Data from our laboratory and 3156 BRIEF REVIEWS: IL-17 ACTIVITIES IN THE KIDNEY others have shown that both kidney infiltrating CD4+ and gd+ immune response (58). Similar to IL-17, other IL-17 family T cells produce IL-17 in response to kidney injury (43, 50). members have been implicated in autoimmune kidney Indeed, a series of studies involving mouse models of various diseases. Mice deficient in IL-17F and IL-17C signaling forms of autoimmune glomerulonephritis have provided showed ameliorated renal pathology in mouse model of evidence for functional importance of IL-17 in disease experimental crescentic and ANCA-associated glomerulonephritis, pathogenesis. For example, studies in mouse models of respectively (59, 60). In two independent studies, polymorphism crescentic glomerulonephritis and nephrotoxic nephritis in the IL-17 pathway genes has been linked to the risk of showed that IL-23/Th17 axis and IL-17 are absolutely chronic kidney disease. An association was identified between required for renal dysfunction and pathogenesis (51, 52). allele rs4819554 A, part of the IL-17RA , and risk of Interestingly, ameliorated renal pathology observed in developing end stage renal disease and increased expression of 2 2 2 2 the IL-23p19 / and IL-17 / mice are independent of IL-17RA and Th17 cell frequency (61, 62). Th1 response, thus arguing against the longstanding notion IL-17RA is used by all the IL-17 family members for sig- that glomerulonephritis is a Th1-mediated disease. IL-17, naling (4). Although IL-17RA is ubiquitously expressed, the along with TNF-a (a cytokine with which IL-17 exhibits majority of the studies showed that IL-17R signaling is mostly profound synergy), drives the expression of restricted to cells of nonhematopoietic origin. Accordingly, we 2 2 signals such CCL20 from renal tubular epithelial cells, found that IL-17RA / mice were protected from autoim- required for the infiltration of CCR6+ Th17 and T mune glomerulonephritis, as evident by reduced glomerular regulatory cells in the kidney (43). Subsequently, by taking crescent formation, tubulointerstitial inflammation, and Downloaded from 2 2 advantage of p40 / (mice deficient in both IL-12 and IL- neutrophil influx in the kidney (50). Interestingly, systemic 2 2 2 2 23), p35 / (mice deficient in IL-12 only), and p19 / and humoral immunity was not affected in the absence (mice deficient in IL-23 only), the relative contribution of of IL-17R signaling, suggesting that IL-17RA might be a IL-12 and IL-23 was interrogated in a mouse model promising therapeutic target with minimal adverse effects Goodpasture disease. Knockout of IL-23, but not IL-12, led (50). In contrast, another study showed that IL-17RA defi- to the diminished proliferation and activation of alpha 3 type IV ciency protected mice from crescent formation but not from http://www.jimmunol.org/ collagen-specific T and B cells and reduced cytokine and Ab glomerular necrosis or renal interstitial injury. Investigation of production by immune cells (52). As a result, disease severity bone marrow chimeras to identify the IL-17 target cell types was significantly diminished in mice deficient in IL-23 in glomerulonephritis revealed similar contributions of IL-17 signaling. Using a mouse model of –planted Ag on signaling in hematopoietic and nonhematopoietic cells in the the glomerular basement membrane, it was shown that both pathogenesis of glomerular pathology (63). However, the role Th1 and Th17 cells can mediate renal injury (53). However, of humoral immunity remains controversial and the exact the immunopathological features, time kinetic, and prevalence mechanisms still need to be elucidated.

of certain inflammatory mediators were different in recipient Lupus nephritis. Lupus nephritis is a severe clinical manifesta- by guest on September 25, 2021 mice receiving either Th1 or Th17 cells. Th17 cells induced the tion of systemic lupus erythematous and affects up to 60% of expression of chemokines necessary for neutrophil infiltration patients (64). Although experimental evidence suggests a and causing early kidney pathology. These results support a pathogenic role for IL-17 in mouse models of experimental report showing that IL-17 promotes early but attenuates glomerulonephritis, the contribution of IL-17 in lupus established disease in crescentic glomerulonephritis in mice nephritis is an active area of debate. IL-17–producing 2 2 (54). In contrast, Th1 cell recipients showed more of a double-negative T cells (CD3+CD4 CD8 ) were detected dominated renal injury at later time points. in the nephritic kidneys of MRL/lpr mouse and lupus Following glomerulonephritis, renal infiltration of Th17 patients (65, 66). Using MHC class II tetramers, Kattah cells peaks at day 10 after glomerular injury, followed by et al. (67) identified IL-17–producing CD4+ T cells specific a decline in the number in course of disease. In contrast, for spliceosomal protein U1-70 in MRL/lpr mice. Subsequent Th1 cells and T regulatory cells infiltrate the kidney at later studies demonstrated that omission of the IL-23R protected stages. The mechanisms for differential infiltration of various B6/lpr mice from lupus nephritis and that transfer of IL-23– subsets of CD4+ T cells are poorly understood. However, treated lymph node cells from B6/lpr mice induced lupus 2 2 careful analyses of multiple IL-17 reporter mice revealed nephritis in Rag1 / mice (68). Studies by our group and that Th17 cells are very stable and do not show signs of others have also implicated Th17 cells and IL-17 in the transdifferentiation to IFN-g+ or T regulatory cells in the development of proliferative glomerulonephritis in MRL/lpr nephritic kidneys (55). Recently, the migration of Th17 cell mice (69, 70). IL-17 cytokines and their signaling via the from the intestine to nephritic kidney has been elegantly adaptor protein Act1 contributes to lethal pathology in an demonstrated in a photoconvertible Kaede mice (56), FcgR2b-deficient mouse model of lupus nephritis (71). indicating that intestinal microbiome may impact Th17- Moreover, studies in autoimmune prone BXD2 mice showed dominated kidney diseases. Mice deficient in T-bet and that IL-17 and Th17 cells orchestrate autoreactive germinal consequently in Th1 cells showed diminished nephritis center formation and, consequently, lupus-like disease despite enhanced Th17 response, suggesting that Th1 cells development (72). In the pristine-induced model of lupus are required for Th17 cell–driven nephritis (57). Finally, a nephritis, lack of IL-17A or IL-17F ameliorated disease crucial role for IL-17 as a mediator of renal tissue damage was severity (70, 73). We showed that cross-talk between also demonstrated in a murine model of antineutrophilic complement component C5a and Th17 cells is required to cytoplasmic Ab (ANCA)–associated vasculitis. In this study, inhibit Th17-suppressive type I IFN signals and pathogenesis IL-17 knockout mice were protected from kidney injury due of pristine-induced lupus nephritis (74–76). However, to impairment of both the innate and the adaptive arms of the nagging discrepancies exist against these interpretations. In a The Journal of Immunology 3157 recent study, IL-17 deficiency or neutralization of IL-17 What factor dictates which one or the other overcomes re- demonstrated minimal impact on the development of mains to be precisely defined in the kidney. IL-17 causes proliferative glomerulonephritis in MRL/lpr mice or NZB/ autoimmune diseases but is also implicated in mediating NZW mice, respectively (77). The frequency of kidney protection against antimicrobial infections. Thus, it is imperative infiltrating IL-17–producing double-negative T cells and to understand how IL-17, which protects kidney from infections, CD4+ T cells was scant compared with the number of IFN-g+ is rendered harmful in the presence of autoinflammatory cells, indicating a predominance of the Th1 immune response conditions. Abs to IL-17 and IL-17RA are currently approved in these models of lupus nephritis. The reasons for the for the treatment of (87, 88). Several other clinical apparent disagreement between these findings are currently trials (∼90 trials) are currently ongoing that target various unclear. However, difference in genetic backgrounds and IL-17 pathway molecules in autoimmune diseases (https:// microbiome population may account for the discordance www.clinicaltrials.gov). Therefore, answering these questions observed between these findings and require careful evaluation is crucial to developing anti–IL-17–based therapies for auto- in the near future. immune kidney diseases. Because IL-17 is a key determinant Multiple studies showed that patients with lupus exhibit of local renal immunity processes, such interventions should elevated serum levels of IL-17, increased numbers of circu- be cautiously designed. lating IL-17–producing T cells, and increased IL-17 pro- duction by lymphocytes compared with age- and sex-matched Acknowledgments healthy volunteers (65, 78). In some, but not all, cases, IL-17 We thank Biswas laboratory members for helpful suggestions and discussions. Downloaded from serum levels correlated with lupus disease activity (78, 79). The number of Th17 cells in the peripheral blood of lupus patients increased during flares and decreased following suc- Disclosures cessful treatment (79). Another study demonstrated that The authors have no financial conflicts of interest. 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