Progranulin: A key player in autoimmune diseases

Cytokine xxx (2016) xxx–xxx

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Cytokine journal homepage: www.journals.elsevier.com/cytokine

Review article

Progranulin: A key player in autoimmune diseases Jinlong Jian a, Guangfei Li a,b, Aubryanna Hettinghouse a, Chuanju Liu a,c,⇑ a

Department of Orthopedics Surgery, New York University School of Medicine, New York, NY 10003, United States Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China c Department of Cell Biology, New York University School of Medicine, New York, NY 10016, United States b

a r t i c l e

i n f o

a b s t r a c t

Article history: Received 30 April 2016 Received in revised form 3 August 2016 Accepted 6 August 2016 Available online xxxx

Autoimmune disease encompasses an array of conditions with a variety of presentations and the involvement of multiple organs. Though the etiologies of many autoimmune conditions are unclear, uncontrolled inflammatory immune response is believed to be a major cause of disease development and progression. Progranulin (PGRN), an anti-inflammatory molecule with therapeutic effect in inflammatory arthritis, was identified as an endogenous antagonist of TNFa by competitively binding to TNFR. PGRN exerts its anti-inflammatory activity through multiple pathways, including induction of Treg differentiation and IL-10 expression and inhibition of chemokine release from macrophages. In addition, the protective role of PGRN has also been demonstrated in osteoarthritis, inflammatory bowel disease, and psoriasis. Intriguingly, PGRN was reported to contribute to development of insulin resistance in highfat diet induced diabetes. Emerging evidences indicate that PGRN may also be associated with various autoimmune diseases, including systemic lupus erythematous, systemic sclerosis, multiple sclerosis and Sjogren’s syndrome. This review summarizes recent studies of PGRN as a novel target molecule in the field of autoimmune disease, and provides updated information to inspire future studies. Ó 2016 Published by Elsevier Ltd.

Keywords: Progranulin TNF TNFR Autoimmune diseases

Contents 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

Introduction . . . . . . . . . . . . . . . . Rheumatoid Arthritis . . . . . . . . . Osteoarthritis . . . . . . . . . . . . . . . Inflammatory bowel disease . . . Psoriasis . . . . . . . . . . . . . . . . . . . Diabetes mellitus . . . . . . . . . . . . Systemic Lupus Erythematosus . Systemic sclerosis. . . . . . . . . . . . Multiple sclerosis . . . . . . . . . . . . Sjogren’s syndrome . . . . . . . . . . PGRN autoantibody . . . . . . . . . . Acknowledgments . . . . . . . . . . . References . . . . . . . . . . . . . . . . .

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1. Introduction Inflammation is a normal protective response to pathogen exposure, cell injuries and stress in human and animal physiology. ⇑ Corresponding author at: Rm 1608, Hospital Joint Diseases, New York University School of Medicine, 301 East 17th Street, New York, NY 10003, United States. E-mail address: [email protected] (C. Liu).

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However, dysregulation of the magnitude and duration of inflammatory reaction leads to tissue damage. Cytokines, a group of small proteins that are released from leukocytes or stromal cells, are major mediators in the initiation of inflammatory response. Among these cytokines, tumor-necrosis-factor a (TNF-a) is at the peak of the inflammatory cascade, and increased levels of TNF correlate with inflammation in various diseases, including rheumatoid arthritis, systemic lupus erythematosus, and contact dermatitis.

http://dx.doi.org/10.1016/j.cyto.2016.08.007 1043-4666/Ó 2016 Published by Elsevier Ltd.

Please cite this article in press as: J. Jian et al., Progranulin: A key player in autoimmune diseases, Cytokine (2016), http://dx.doi.org/10.1016/j. cyto.2016.08.007

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Blockade of TNF by its specific antibodies or soluble receptors has been accepted as an effective biological treatment approach for multiple autoimmune and inflammatory diseases, in particular rheumatoid arthritis. Negative regulatory mechanisms have evolved to limit inflammatory response. For instance, regulatory T cells (Treg), a subpopulation of T cells, are immunosuppressive and function to suppress self-reactivity under healthy conditions. IL-10 is an antiinflammatory cytokine and mice deficient in IL-10 develop many types of autoimmune disorders spontaneously. Progranulin (PGRN), also known as granulin–epithelin precursor (GEP) [1], proepithelin (PEPI) [2,3], acrogranin [4], and GP88/PC-cell derived growth factor (PCDGF) [5], is a 593-amino-acid secretory growth factor which was originally identified as a growth factor involved in the promotion of epithelial cell proliferation and wound healing [6]. PGRN is also important in regulating inflammation, at least in part, by directly binding to tumor-necrosis-factor receptors (TNFR) and counteracting the TNF-mediated inflammatory signaling pathway [7]. PGRN contains seven-and-a-half cysteine-rich motifs [8], and it can be degraded by various proteinases, including matrix metalloproteinase (MMP) 9, 12, and 14, ADAMTS-7, elastase, and Proteinase-3 [5,9–12]. Importantly, the degraded fragments of PGRN, or GRNs, are pro-inflammatory and may neutralize intact PGRN’s anti-inflammatory activities [5]. Since its initial discovery, PGRN has been revealed to be an important molecule in a wide variety of disease processes. PGRN level is considered a prognostic biomarker for many forms of cancer as PGRN overexpression associated with cancer cell proliferation and migration [13–15]. GRN gene mutations cause frontotemporal lobular dementia [16,17]. PGRN functions as an important neurotropic factor, and its insufficiency is associated with many other neurodegenerative diseases, such as Parkinson’s disease, Creutzfeldt-Jakob disease, motor neuron disease, and Alzheimer’s disease [18–21]. PGRN has been extensively reviewed as a growth factor and neurotropic factor. This review paper instead focuses on recent updates of PGRN’s role in autoimmune diseases. PGRN binds to TNFR1 with binding affinity comparable to that of TNFa, and binds to TNFR2 with much higher affinity than TNFa [7]. Granulin F, A, C domains mediate the interaction between PGRN and TNFR [7]. A PGRN-derived engineered molecule, called Atsttrin, containing half units of GRNs F, A, and C and their linker regions, also showed clear binding to TNFR1/2 and effective inhibition of TNF-induced inflammation [7]. Subsequent studies indicated that PGRN bound to the CRD2 and CRD3 domains of TNFR1/2 [22]. Increasing evidences specify that TNFR1 and TNFR2 mediate different signaling pathways and play distinct roles in various pathophysiological conditions [23,24]. TNFR1 signaling induces the apoptotic pathway while TNFR2 signaling triggers cell survival signaling [24]. PGRN not only blocks the TNF-induced inflammatory pathway by competitively binding to TNFR1, but also binds to TNFR2 to promote cell proliferation. In addition to TNFR, death receptor 3 (DR3), the highest homolog of TNFR1, was also isolated as a PGRN and Atsttrin binding receptor in a protein-protein interaction screen between PGRN and all TNFR superfamily members [25]. PGRN and Atsttrin inhibit the binding of DR3 to TL1A, the only known ligand of DR3. Similar to TNF/ TNFR1, TL1A/DR3 is also involved in the process of various inflammatory disorders [26,27]. In addition to binding to TNFR1/2 and DR3, PGRN induces Treg populations and IL-10 production [7,28,29] and inhibits chemokine release [30]. In this review, we start with a recent update of the anti-inflammatory function of PGRN in RA, osteoarthritis (OA), inflammatory bowel diseases (IBD), and psoriasis. We will also summarize relevant findings from additional autoimmune diseases in which PGRN may function as a contributory factor. Lastly, we will discuss the exciting discovery of

a PGRN autoantibody and its clinical relevance to autoimmune diseases. 2. Rheumatoid Arthritis Rheumatoid Arthritis (RA) is a systemic autoimmune disorder that primarily affects the joints, with the wrists and hands most commonly affected. Patients of RA present with swollen, warm, and painful joints. Although the cause of RA is still unclear, it is believed that TNF-a driven inflammation plays a critical role, and TNF inhibitors are regarded as the most effective treatments for RA [31]. Recently, PGRN was found to be an endogenous antagonist of TNFa through competitively binding to TNFR [7]. Under a collagen-induced arthritis (CIA) model, PGRN null (PGRN / ) mice exhibit a higher incidence of arthritis and a more severe phenotype [7], however, administration of recombinant PGRN protein inhibits disease progression in these PGRN-deficient mice. These data demonstrate that the loss of PGRN expression in vivo results in hyper-susceptibility to collagen-induced arthritis, a well-accepted model of inflammatory arthritis, which can be reversed by the administration of recombinant PGRN. Deletion of one or both copies of the GRN gene in TNFtransgenic (TNF-Tg) mice, which develop an inflammatory arthritis phenotype spontaneously [32,33], significantly accelerates the onset of arthritis [7]. Pathologically, TNF-Tg mice with deletion of one or both alleles of PGRN exhibit significantly increased synovitis, pannus formation, destruction of the ankle joints, and loss of cartilage matrix [7]. In a collagen-induced arthritis model of RA, treatment of PGRN-deficient TNF-Tg mice with recombinant PGRN protein resulted in an interruption of disease progression and a dramatically reduced arthritis clinical score. Interestingly, at 7 days following the cessation of PGRN treatment, signs of arthritis relapsed. Taken together, these data suggest that PGRN exerts its anti-inflammatory effects through the inhibition of TNF/TNFR signaling in vivo. Importantly, PGRN-derived Atsttrin was shown to be even more effective than PGRN in preventing inflammation in several inflammatory arthritis models [7]. Recently, the clinical relevance of PGRN in RA has been reported by several groups [34–36]. Research teams consistently report elevated serum levels of PGRN in RA patients, as compared to healthy controls, independent of sex and age [34,35]. Interestingly, the balance between PGRN and TNF seems to be important in RA progression, as the ratio of PGRN/TNF is closely correlated with RA stages [34]. Moreover, PGRN levels in synovial fluid are also significantly higher in RA patients than in OA patients [33,34]. Immunohistological analysis of synovial tissue from patients with RA has confirmed significant upregulation of PGRN in infiltrating inflammatory cells, especially in the sublining layer [35]. The immunosuppressive activity of PGRN is exemplified through PGRN’s stimulatory effect on Treg cell population [7,28]. A recent study has also reported that both PGRN level and human B regulatory (Breg) cell population were significantly higher in RA patients. However, the number of Breg cells was not correlated to PGRN level [36], suggesting that PGRN and Breg cell population may be independently altered in RA. 3. Osteoarthritis Osteoarthritis (OA), the most common joint disease, is a slowprogressing degenerative disease characterized by cartilage loss. Originally, mechanical wear and tear was considered paramount in OA etiology. However, increasing evidence indicates that growth factors and cytokines are strongly implicated in initiating and aggravating OA lesions [37]. PGRN was isolated as one such growth factor in a genome-wide screen for genes differentially expressed

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in OA [38]. Aged PGRN knockout (KO) mice develop OA-like phenotypes featuring exaggerated breakdown of cartilage structure and OA progression [39]. PGRN KO mice also show a severe OA phenotype in surgically-induced OA models [40] and both recombinant PGRN and PGRN-derived Atsttrin attenuated degradation of cartilage matrix and protected against OA development in these models [39,43]. Mesenchymal stem cells (MSCs) stably transfected to express recombinant Atsttrin (MSC-Atsttrin) intra-articularly injected one week after surgery significantly suppressed TNFadriven up-regulation of matrix proteases and inflammatory factors and prevented the progression of degenerative changes in the surgically induced anterior cruciate ligament transection (ACLT) murine model of OA [41]. Recently, it was reported that intra-articular injection of etanercept (sTNFR2), known to be effective in treating patients with RA [42], caused more severe joint destruction in a mouse model of OA [43,44]. Importantly, sTNFR2 is not a TNFa-specific inhibitor; it is also a PGRN blocker. sTNFR2 likely inhibits PGRN much more efficiently than it inhibits TNFa, since PGRN exhibits an approximately 600-fold higher binding affinity than TNF-a to TNFR2 [7]. Accordingly, these seemingly paradoxical results may be explained through the importance of PGRN’s protective role in the pathogenesis of OA [45]. In primary chondrocytes, PGRN activates the ERK2 pathway and anabolic biomarkers through the TNFR2 pathway [41]. Additionally, PGRN suppresses inflammatory action of TNF-a and inhibits the activation of b-Catenin signaling in cartilage and chondrocytes [41]. PGRN expression was induced during chondrocyte differentiation in vitro, as well as in primary chondrocytes, infrapatellar fat pads (IPFPs) and synovial tissues of OA patients [46]. In addition to binding to TNFR2 to trigger the anabolic pathway, PGRN was found to inhibit IL-1b and LPS mediated signaling in chondrocytes [46]. PGRN inhibited IL-1b and LPS mediated chondrocyte catabolism, including suppression of expression of NOS2, COX-2, MMP13 and VCAM-1. The inhibition of IL-1b by PGRN was abolished following knockdown TNFR1 by RNA interference. Therefore, PGRN does not directly block activation of toll-like receptor 4 (TLR4) by LPS or induction of IL-1b, but inhibits inflammation in response to IL-1b and TLR4 stimulation through binding to TNFR1 and blocking TNF-a mediated activation of the NF-jB directed immune response [46]. This interesting study provides novel insight into the mechanisms of PGRN’s anti-inflammatory function in OA. At least two pathways are involved: (a) PGRN binds to TNFR2 and induces anabolic metabolism in chondrocytes, and (b) PGRN inhibits IL-1bmediated catabolic metabolism by blocking TNFR1. Therefore PGRN is a promising target molecule for drug development against OA. Indeed, Liu et al. have reported that recombinant PGRN protein attenuated degradation of cartilage matrix and protected against OA development in surgical-induced OA models [47]. PGRNderived Atsttrin also gave rise to a promising effect in treating OA in a surgically-induced mouse model [41].

4. Inflammatory bowel disease Inflammatory bowel disease (IBD) includes a range of conditions characterized by chronic inflammation of the gastrointestinal tract, of which ulcerative colitis and Crohn’s disease are the two most prevalent entities. IBD is an autoimmune disorder with unclear etiology. Pathologically, IBD is characterized by infiltration of inflammatory cells into the intestine and subsequent chronic inflammation. TNF is considered a major mediator of IBD and anti-TNF therapy has been successfully used to treat IBD [48]. Both human and animal data clearly indicate a close association between TNF-antagonist PGRN and IBD. Neutralizing

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autoantibodies against PGRN (PGRN-Abs) have been identified in the sera of patients with various autoimmune disorders [49], including IBD [50]. PGRN autoantibodies were detected in 16.31% of patients with Crohn’s disease and 21.13% of patients with ulcerative colitis [50]. These PGRN-Abs demonstrated significant neutralizing effects on PGRN plasma levels. PGRN-Abs also displayed a clear pro-inflammatory effect, evidenced by a correlation between PGRN-antibodies and TNF-a-induced downmodulation of FOXP3 in CD4+CD25hi Treg cells and between PGRN-Abs and TNF-a-induced cytotoxicity of human colon adenocarcinoma HT29 cells [50]. Wei et al. have reported elevated levels of PGRN relative to healthy controls in both human samples from IBD patients and mouse colitis models induced by dextran sulfate sodium (DSS) [29]. Moreover, PGRN null mice are highly susceptible to DSS- or picrylsulfonic acid (TNBS)-induced colitis and administration of recombinant PGRN is able to reduce the disease severity score in each model [29]. Recombinant PGRN protein is protective in colitis through the IL-10 and TNFR2 pathway, as indicated by attenuated therapeutic effect in IL-10 null mice or in the presence of neutralizing IL-10R antibody, and in TNFR2 deficient mice [29]. In this study, PGRN also significantly induced Treg population and slightly reduced Th17 population [29]. In sum, PGRN and PGRN-derived Atsttrin inhibit both TNF/TNFR and TL1A/DR3 inflammatory signaling in vitro and in vivo by competitively binding to TNFR1 and DR3 [25]. In vitro, Atsttrin dosedependently suppresses the expression of TL1A target genes and blocks TL1A-mediated osteoclastogenesis. Importantly, in the DSS-induced murine colitis model, injection of PGRN-derived Atsttrin also significantly inhibited inflammation and attenuated body weight loss and rectal bleeding [25]. These data support the involvement of both TL1A/DR3 and TNF/TNFR signaling in colitis and suggest that PGRN-derived biologics, like Atsttrin, represent promising therapeutic target. Application of recombinant PGRN protein to treat these diseases has shown promising therapeutic effect. However, direct use of full-length PGRN does carry caveats; for example, PGRN promotes cancer cell growth and ought not be used in cancer patients with autoimmune diseases. Additionally, PGRN induces insulin resistance in animal models [51], which may further limit its application in humans. Therefore, developing a PGRN-derived small peptide that retains therapeutic effect but does not exhibit other biological activities of PGRN presents an optimal strategy for drug development against autoimmune diseases.

5. Psoriasis Psoriasis is a chronic autoimmune disorder affecting the skin, marked by epidermal hyperproliferation, inflammation, and angioneogenesis. Psoriasis is initiated and perpetuated through dysregulated interaction between the adaptive and innate immune system [52]. Both serum level and skin expression of PGRN are elevated in psoriasis vulgaris, and serum PGRN/TNFa ratio is negatively correlated with disease severity [53]. PGRN expression is induced in wild type (WT) mice under the 12-O-tet radecanoylphorbol-13-acetate (TPA)-induced skin lesion model, and TPA exposure generates a greater incidence of psoriasislike inflammation in PGRN knockout (KO) mice relative to WT mice [53]. PGRN KO mice have reduced differentiation of regulatory T cells in lymph nodes and decreased recruitment of these cells in the affected skin [53]. These results are consistent with those reported by Zhao et al. [54], detailing severe inflammation induced by oxazolone in PGRN KO mice. In Zhao et al.’s model, Atsttrin effectively inhibited the skin inflammation induced by oxazolone [54].

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6. Diabetes mellitus Diabetes mellitus (DM) is an autoimmune disorder characterized by persistent elevation of blood glucose levels caused either by insufficient insulin production in the pancreases (type 1) or insensitivity to insulin in peripheral tissues (type 2). There is also a third type, distinguished by insulin insensitivity during pregnancy without diabetic condition prior to pregnancy, called gestational diabetes mellitus. Circulating PGRN significantly correlates with markers of diabetes including BMI, macrophage infiltration in omental adipose tissue, serum C-reactive protein (CRP) concentrations, HbA1C values, and total cholesterol [55]. Further, it was revealed that serum level of PGRN is increased in type 2 DM patients compared with healthy controls [55]. PGRN level in these type 2 DM patients was significantly reduced after 4 months of physical training [55]. Additionally, type 2 DM patients who were under 2-year Dietary Intervention Randomized Controlled Trial (DIRECT) of low-fat, mediterranean, or low-carbohydrate diets for weight loss also show reduced serum levels of PGRN, and other adipokines, including hsCRP, HDL-C, adiponectin, fetuin-A, and vaspin [55]. The correlation between PGRN and type 2 DM, reported in Korean populations by Youn et al., was also confirmed in Chinese populations [56], verifying the correlation and indicating that the relationship is not population specific. Furthermore, Flehmig et al. investigated the expression patterns of 20 adipokines across parameters of obesity, glucose metabolism, insulin sensitivity and inflammation and logistic regression analyses revealed ANGPTL6, DLK1, Nampt and PGRN as the strongest adipokine correlates of type 2 DM in obese individuals [57]. In another study, after adjusting for BMI and gender, circulating PGRN was associated with obesity and glucose homeostasis and may predict resting metabolic rate independent of confounder factors, such as triglycerides (TG), HDL, and hs-CRP [58]. Collectively, these data suggest that PGRN may contribute to the progression of type 2 DM. In an effort to identify novel adipokines implicated in DM, Matsubara et al. isolated PGRN following induction of an in vitro cellular insulin resistance model [59]. Subsequent in vivo study of murine high-fat diet induced diabetes revealed elevated PGRN levels in the blood and adipose tissue. PGRN knockout (KO) mice were resistant to high-fat diet induced insulin resistance, adipocyte hypertrophy and obesity. Furthermore, injection of PGRN protein produced insulin resistance and this effect could be suppressed by neutralizing IL-6 antibody in these mice [59]. In a separate study, Wu et al. found that mice injected with PGRN for 21 days exhibited impaired glucose tolerance and insulin sensitivity [51]. PGRN attenuated insulin signaling via inhibiting mTOR pathway [51]. Blockade of TNFR1 signaling pathway by Fcfused TNFR1 blocking peptide resulted in the restoration of impaired insulin sensitivity and insulin signaling induced by PGRN [51]. Injection of PGRN also leads to an imbalance of autophagy and defective insulin signaling in hepatocytes; TNFR1 blocking peptide completely blocked the interaction between PGRN and TNFR1 and recovered autophagy imbalance and insulin signaling [60]. PGRN was also found to cause insulin resistance and ER stress in the liver and adipose tissue, but not in skeleton muscle [61]. Injection of phenyl butyric acid (PBA), a chemical chaperone capable of alleviating ER stress, resulted in a significant restoration of systemic insulin sensitivity and recovery of insulin signaling [61]. The pancreatic ER kinase, or PKR-like kinase (PERK), is an ER transmembrane protein kinase that phosphorylates a subunit of translation initiation factor 2 (eIF2a) in response to ER stress. Blockade of PERK partially restored PGRN-induced insulin resistance and reduced ER stress [61]. In a follow-up study, Wu et al. also showed that PGRN-induced ER stress depends on TNFR1 [62]. These in vivo and in vitro discoveries by Wu et al. are also supported by a continuation study using human samples. Serum levels

of PGRN positively correlated with BMI, waist circumference, fasting insulin, fasting plasma glucose, glycated hemoglobin A1c, triglyceride, and homeostasis model assessment of insulin resistance. Increased PGRN also associated with autophagy marker proteins, LC3 and Atg, in omental adipose tissue [62]. Taken together, PGRN-induced insulin resistance results mechanistically through up-regulation of IL-6 production, ER stress, and imbalance of autophagy pathway in a TNFR1-depednent manner. In addition to promoting insulin resistance and the development of DM, PGRN is also closely correlated with complications of DM. High glucose levels directly damage small vessels in multiple organs and lead to a wide range of complications characteristic of DM (including nephropathy, retinopathy, neuropathy, cardiovascular diseases, etc.). Diabetic nephropathy is the most common complication of DM and chronic renal failure will occur without proper DM management. Richter et al. have reported that PGRN levels increased along with the stages of chronic kidney disease [63]. It is hypothesized, by Richter et al., that increased level of PGRN may be due to reduced elimination of PGRN in urine [63]. However a direct correlation between reduced urinary excretion of PGRN and increased serum PGRN level has not been demonstrated [64]. Another group also reported that PGRN is associated with microvascular complications in type 2 DM [65]. Serum level of PGRN is significantly increased in DM patients with microangiopathies, including clinical diabetic nephropathy and proliferative diabetic retinopathy [65]. Serum levels of PGRN are independently correlated with urinary albumin excretion rate and creatine, suggesting a correlation between PGRN serum level and severe kidney damage [65]. However, it is still unknown whether increased PGRN is the cause or result of renal damage and more studies are needed to elucidate the underlying connection between PGRN and DM complications. In the case of gestational diabetes mellitus, PGRN levels have been reported to be significantly higher in women during pregnancy as compared with post-partum levels [66]. Multivariate regression analyses showed a strong positive correlation of PGRN with estrogen and progesterone. Interestingly, PGRN levels are rapidly reduced after pregnancy regardless of the gestational glucose tolerance state [66]. Therefore, it is suggested that increased PGRN associated with pregnancy is likely due to hormonal changes, and it is not the cause of gestational diabetes mellitus.

7. Systemic Lupus Erythematosus Systemic Lupus Erythematosus (SLE) is a chronic inflammation in multiple organs including the skin, kidney, brain, lung, and other organs. While the exact etiology is unclear, SLE manifests as systemic immunological abnormalities, particularly involving the production of a number of antibodies against self-antigens, which triggers inflammation and tissue damage. Recently, serum PGRN levels were found to be significantly higher in SLE patients than in healthy controls and PGRN level was associated with activity of clinical symptoms and disease severity, and moreover, PGRN level significantly decreased after successful treatment of SLE [67]. Qiu et al. likewise reported that PGRN serum levels were significantly higher in pre-treated SLE patients, compared with health controls and that PGRN levels were reduced following prednisone treatment [68]. The serum level of PGRN also correlated with pro-inflammatory cytokines IL-6 and TNF-a, and titer of antidsDNA antibody [68]. Further, PGRN is reportedly induced in lupus nephritis, a type of SLE. Overexpression of PGRN remarkably exacerbated lupus nephritis, while down-regulation of PGRN with shRNA ameliorated the condition [69]. These data suggest PGRN may be involved in the progression of SLE. Intriguingly, Thurner

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et al. have reported that autoantibody against PGRN was found in many autoimmune diseases, including SLE [49], and presence of this autoantibody reduced serum levels of PGRN [49,70]. Additional studies with large sample sizes are needed to further determine the function of PGRN in SLE. 8. Systemic sclerosis Systemic sclerosis (SS) is a multisystem connective tissue disease characterized by immune abnormalities, vasculopathy, and fibrosis of the skin and certain internal organs. Though the etiology of SS is unclear, pathologically it is characterized by collagen deposition in multiple organs [71]. In a comparison of 60 SS patients and 16 healthy controls, PGRN was significantly higher in epidermis and dermis of SS patients, and the expression level was inversely correlated with disease duration [71]. A deficiency of Fli-1 transcription factor in SS was found to be responsible for the increased expression of PGRN. Gene silencing of Fli-1 resulted in a significant increase in PGRN mRNA levels in normal dermal fibroblasts. Fli-1 directly bound to GRN promoter region and repressed PGRN production [72]. In a bleomycin-induced skin SS model, both PGRN and TNF are elevated [72]. As TNF has a strong antifibrotic effect through counteracting the TGF-b pathway and collagen synthesis [73–75], increased PGRN in SS patients confers resistance to TNF-mediated inhibition of collagen expression, and knockdown of PGRN by siRNA has been shown to restore the inhibitory activity of TNF in SS fibroblasts [72]. Interestingly, it has been reported that decoy receptor 3 (DcR3) is also increased in SS patients compared with healthy controls [76]. DcR3 competes with death receptors for ligand binding, including TL1A, which inhibits pathological angiogenesis in SS. Therefore, increased DcR3 may promote the progression of SS by neutralizing TL1A function [77]. PGRN also inhibits the binding of TL1A to DR3 [25]. It is, thus, conceivable that elevated expression of PGRN in SS, not only neutralizes the anti-fibrotic effect of TNF [72], but may also block the anti-angiogenesis effect of TL1A. 9. Multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease with effects upon the central nervous system characterized by demyelination of neuronal axons. Patients usually experience a remissionrelapse pattern in the progression of MS. When examining postmortem tissue of 19 MS and six control brains, Vercellino et al. reported that PGRN is strongly expressed in MS brain tissue: in the demyelinating lesion, PGRN is expressed in macrophages/ microglia, and in normal-appearing lesion, PGRN is expressed in activated microglia and neurons [19]. In control brains, PGRN is only expressed in the neuron. Moreover, comparison of PGRN levels in the cerebrospinal fluid (CSF) of 40 MS patients, 15 noninflammation controls, and 5 inflammation controls (viral encephalitis) revealed that PGRN concentrations were significantly higher in during MS relapse and in patients with progressive MS, as compared with CSF-PGRN concentrations of MS patients in remission and with non-inflammatory controls [19], suggesting that PGRN levels in CSF may be a promising marker for active MS. The linkage between MS and PGRN is also supported by genetic variation analysis. When comparing GRN gene (coding PGRN) variability between 354 MS and 343 control samples, no significant associations were found. However, after stratifying according to MS subtypes, a significantly increased frequency of the rs2879096 TT genotype was found in primary progressive MS (PPMS) compared with healthy controls [78]. Stratifying according to gender, an association with rs4792938 C allele and rs2879096 T allele were found in male PPMS patients compared with controls.

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Haplotype analysis showed that frequency of TC haplotype of rs2879096 and rs4792938 are increased in PPMS male patients compared with male controls [78]. In a separate study, genetic variability across 400 MS patients was analyzed to explore association between GRN genetic variability and MS severity and relapse recovery; two additional single nucleotide polymorphism (SNP) sites, rs9897526 A allele and rs5848 T allele, were associated with a more severe disease course (Multiple Sclerosis Severity Score > 5), and reduced level of PGRN in serum [79]. The rs5848 T allele is located in the 3-UTR region of PGRN mRNA, and it has been well-established to correlate with reduced level of PGRN in various diseases [80,81]. Based on the genetic evidence, it is clear that PGRN polymorphisms are associated with certain subtypes of MS, as well as with disease severity [78,79]. However, the function of PGRN in the progression of MS is still unclear. As Vercellino et al. originally reported, PGRN is increased in brain tissues and CSF of MS patients [19], however, their follow-up study has shown that the rs5848 T allele is associated with more severe disease and a low level of PGRN in circulation [79]. The discrepancy between these two studies may be due to the source of samples, since they originally tested PGRN levels in CSF but measured serum levels of PGRN in the following study. Indeed, Nicholson et al. have found that circulating PGRN and CSF PGRN are differently regulated [82]. For example, though both plasma and CSF PGRN increase with age, plasma PGRN levels were 7% lower and CSF PGRN levels 5% higher in male compared with female participants. Age, sex, GRN genotype, and plasma PGRN together accounted for only 18% of the variability observed in CSF PGRN [82]. Therefore, CSF PGRN and serum PGRN may have different significance in the etiology and progression of MS, which warrants further study. 10. Sjogren’s syndrome Sjögren’s syndrome is a chronic autoimmune disease in which exocrine glands, such as lacrimal and salivary glands, are damaged by the immune system. This disorder may present as either an isolated syndrome, named primary SS (pSS), or as secondary SS, when observed in association with other connective tissue diseases [83]. Many inflammatory cytokines such as IFN, B-cell-activating factor (BAFF), IL-6, IL-21, and IL-12 are involved in the progress of pSS [83]. Recently, PGRN was also reported to be significantly increased in pSS patients before treatment as compared with healthy controls and that PGRN level reduced, becoming comparable to that of healthy controls, after pSS treatment [84]. It remains to be confirmed whether increased PGRN contributes to the pathogenesis of pSS. 11. PGRN autoantibody The discovery of PGRN autoantibody (PGRN-Ab) in patients with autoimmune diseases is an exciting finding in the field. In an attempt to identify novel autoantibodies associated with vasculitis, Thurner et al. screened a cDNA library with serum from vasculitis patients who have anti-neutrophil cytoplasmic antibodies (ANCA), using ANCA-negative vasculitis serum as a negative control, and found that an antibody against PGRN existed in all four forms of vasculitis: Churge-Strauss syndrome, granulomatosis with polyangiitis, panarteritis nodosa, and giant cell arteritis [48]. An extended screening revealed that the PGRN autoantibody was widely present in a variety of autoimmune diseases, including: 21.5% patients with giant cell arteritis and/or polymyalgia rheumatica, 30.7% patients with Takayasu’s arteritis, 40% patients with classical panarteritis nodosa, 33.3% with Behcet’s disease, 41.3% patients with granulomatosis with polyangiitis, 30.4%

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patients with Churge-Strauss syndrome, 36.8% with microscopic polyangiitis, 42.8% patients with SLE, and 42.8% patients with RA [49]. Epitope mapping located aa12-112, which includes the GRN signal peptide and GRN P and G domains, as the region recognized by the PGRN autoantibody [49]. PGRN autoantibody positive patients have lower serum levels of PGRN, as compared with PGRN autoantibody negative patients. Furthermore, there is a strongly significant association of positive PGRN antibody status and active disease in granulomatosis with polyangiitis [49]. In a separate study, Thurner et al. screened the serum from 260 patients with Psoriatic arthritis (PsA), 100 patients with psoriasis without arthritic manifestations (PsC) and 97 healthy controls. The result show that around 20% PsA patients have the PGRN autoantibody and the presence of the autoantibody is more frequent with patients have enthesitis or dactylitis; the autoantibody was not detected in PsC patients or healthy controls [85]. Moreover, PGRN autoantibody positive PsA patients have relatively

low serum levels of PGRN, and serum positive for PGRN antibody is more pro-inflammatory [85]. Thurner et al. also examined the PGRN autoantibody in IBD patients and found that 16.31% patients with Crohn’s disease and 21.13% patients with ulcerative colitis are positive for the PGRN autoantibody [49]. Notably, PGRN autoantibodies also have significant neutralizing activity against plasma PGRN. Serum positive for PGRN autoantibody has less anti-TNFmediated cytotoxicity effect, and enhanced TNF-a-induced downmodulation of FOXP3 in CD4+CD25hi Treg [50]. Subsequently, Thurner et al. compared PGRN protein between PGRN autoantibody positive serum and PGRN autoantibody negative serum by isoelectric focusing, and they found that there are two bands in PGRN-Ab positive patient samples. This additional band represents hyperphosphorylation of PGRN at Ser81 [70]. Phosphorylation of Ser81 of PGRN is mediated by PKCb1 and dephosphorylation is mediated by PP1. Phosphorylation of Ser81 prevents interaction with and inhibition of TNFR1, TNFR2 and

Table 1 Function of PGRN in autoimmune diseases and its underlying mechanism. Function

Mechanism

Ref.

RA

Inhibit RA disease progression

[7,28]

OA

Protect against OA development

IBD Psoriasis Diabetes mellitus

Anti-inflammation function Anti-inflammation function Induce insulin resistance and impaired glucose tolerance

SLE

Levels of PGRN correlated with disease severity, and levels reduced after treatment May promote disease progression by increasing collagen deposition Levels of PGRN in brain tissue and CSF are increased in MS patients, and GRN gene variants are associated with MS Levels of PGRN are increased and associated with disease severity

Block TNF/TNFR1 signaling Induce Treg population Increase IL-10 production Active TNFR2 anabolic metabolism Inhibit IL-1b-induced catabolism by blocking TNFR1 Induced Treg and IL-10 Stimulate Treg population Upregulate IL-6 production, ER stress and disturbing autophagy pathway in a TNFR1-depednent manner Unclear, PGRN may be induced as a negative feedback to limit inflammation Antagonizing the antifibrotic effect of TNF and blocking anti-angiogenesis effect of TL1A possibly Unclear, PGRN may be induced as a negative feedback to limit inflammation

Systemic sclerosis Multiple sclerosis

Sjogren’s syndrome

Unclear, PGRN may be induced as a negative feedback to limit inflammation

[40,46,86] [29] [54] [51,59–61] [67,68] [72,77] [19,69]

[84]

Sjogren's Syndrome Rheumatoid arthritis Systemic sclerosis

Osteoarthritis

Diabetes Mellitus

Progranulin (PGRN) IBD

Psoriasis SLE Multiple sclerosis

Fig. 1. Illustration of PGRN’s function in autoimmune diseases.

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J. Jian et al. / Cytokine xxx (2016) xxx–xxx

DR3 by PGRN [70], and alters the conversion pattern of PGRN into its small, degraded fragments [70]. These results provide a molecular basis for the production of PGRN-Ab, and how the PGRN-Ab functions as pro-inflammatory molecule. In summary, we present a timely update on the study of PGRN in autoimmune diseases, and conclude that PGRN is a major antiinflammation molecule in multiple diseases, including RA, OA and IBD. However, PGRN may also promote the development of certain diseases, such as DM (Fig. 1). For many autoimmune diseases, the function(s) of PGRN remain unclear (Table 1). It should be noted that currently available ELISA kits cannot distinguish full length PGRN and granulin fragments. In contrast to full-length PGRN, the granulin fragments are believed to be proinflammatory [5]. Accordingly, in some diseases, PGRN may be processed into small granulin fragments, and the granulins, not full length PGRN, contribute to disease development and progression. It is also possible that PGRN has multiple facets and plays different roles in various diseases and conditions. Therefore, as a new molecule associated with the various aforementioned autoimmune diseases, future studies on PGRN may not only provide new insights into the pathogeneses of autoimmune disease, but may also present a new intervention target for treating such disorders and conditions. Acknowledgments This work was supported partly by NIH research Grants R01AR062207, R01AR061484, and R56AI100901 (to C.J. Liu). References [1] T. Zanocco-Marani et al., Biological activities and signaling pathways of the granulin/epithelin precursor, Cancer Res. 59 (1999) 5331–5340. [2] G.D. Plowman et al., The epithelin precursor encodes two proteins with opposing activities on epithelial cell growth, J. Biol. Chem. 267 (1992) 13073– 13078. [3] M. Shoyab, V.L. McDonald, C. Byles, G.J. Todaro, G.D. Plowman, Epithelins 1 and 2: isolation and characterization of two cysteine-rich growth-modulating proteins, Proc. Natl. Acad. Sci. U.S.A. 87 (1990) 7912–7916. [4] O.O. Anakwe, G.L. Gerton, Acrosome biogenesis begins during meiosis: evidence from the synthesis and distribution of an acrosomal glycoprotein, acrogranin, during guinea pig spermatogenesis, Biol. Reprod. 42 (1990) 317– 328. [5] J. Zhu et al., Conversion of proepithelin to epithelins: roles of SLPI and elastase in host defense and wound repair, Cell 111 (2002) 867–878. [6] Z. He, C.H. Ong, J. Halper, A. Bateman, Progranulin is a mediator of the wound response, Nat. Med. 9 (2003) 225–229, http://dx.doi.org/10.1038/nm816. [7] W. Tang et al., The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice, Science 332 (2011) 478– 484, http://dx.doi.org/10.1126/science.1199214. [8] R. Hrabal, Z. Chen, S. James, H.P. Bennett, F. Ni, The hairpin stack fold, a novel protein architecture for a new family of protein growth factors, Nat. Struct. Biol. 3 (1996) 747–752. [9] K. Kessenbrock et al., Proteinase 3 and neutrophil elastase enhance inflammation in mice by inactivating antiinflammatory progranulin, J. Clin. Investig. 118 (2008) 2438–2447, http://dx.doi.org/10.1172/JCI34694. [10] G.S. Butler, R.A. Dean, E.M. Tam, C.M. Overall, Pharmacoproteomics of a metalloproteinase hydroxamate inhibitor in breast cancer cells: dynamics of membrane type 1 matrix metalloproteinase-mediated membrane protein shedding, Mol. Cell. Biol. 28 (2008) 4896–4914, http://dx.doi.org/10.1128/ MCB.01775-07. [11] H.S. Suh, N. Choi, L. Tarassishin, S.C. Lee, Regulation of progranulin expression in human microglia and proteolysis of progranulin by matrix metalloproteinase-12 (MMP-12), PLoS ONE 7 (2012) e35115, http://dx.doi. org/10.1371/journal.pone.0035115. [12] D. Xu et al., Novel MMP-9 substrates in cancer cells revealed by a label-free quantitative proteomics approach, Mol. Cell. Proteomics: MCP 7 (2008) 2215– 2228, http://dx.doi.org/10.1074/mcp.M800095-MCP200. [13] G. Frampton et al., Interleukin-6-driven progranulin expression increases cholangiocarcinoma growth by an Akt-dependent mechanism, Gut 61 (2012) 268–277, http://dx.doi.org/10.1136/gutjnl-2011-300643. [14] L. Diaz-Cueto, F. Arechavaleta-Velasco, A. Diaz-Arizaga, P. Dominguez-Lopez, M. Robles-Flores, PKC signaling is involved in the regulation of progranulin (acrogranin/PC-cell-derived growth factor/granulin-epithelin precursor) protein expression in human ovarian cancer cell lines, Int. J. Gynecol. Cancer 22 (2012) 945–950, http://dx.doi.org/10.1097/IGC.0b013e318253499c.

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Please cite this article in press as: J. Jian et al., Progranulin: A key player in autoimmune diseases, Cytokine (2016), http://dx.doi.org/10.1016/j. cyto.2016.08.007