99 (2017) 139–147

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Cytokine

journal homepage: www.elsevier.com/locate/cytokine

Review article 34, from pathogenesis to clinical applications MARK ⁎ ⁎ Muhammad Baghdadi , Hiraku Endo, Yoshino Tanaka, Haruka Wada, Ken-ichiro Seino

Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Japan

ARTICLE INFO ABSTRACT

Keywords: Interleukin-34 (IL-34) is a hematopoietic cytokine that was described for the first time in 2008 as a second ligand IL-34 of CSF1R in addition to M-CSF. IL-34 and M-CSF share no sequence homology, but have similar functions, Autoimmune diseases affecting the biology of myeloid cell lineage. In contrast to M-CSF, IL-34 shows unique signaling and expression fl In ammation patterns. Physiologically, IL-34 expression is restricted to epidermis and CNS, acting as a regulator of Langerhans Infection cells and microglia, respectively. However, IL-34 expression can be induced and regulated by NF-κB under Cancer pathological conditions. Importantly, growing evidence indicates a correlation between IL-34 and disease se- verity, chronicity and progression. In addition to its promising roles as a novel diagnostic and prognostic bio- marker of disease, IL-34 may also serve as a powerful target for therapeutic intervention. Here, we review the current knowledge regarding the emerging roles of IL-34 in disease, and focus on the clinical applications of IL- 34 in medicine.

1. Introduction unique signaling patterns [4–6]. In contrast to M-CSF, which is ex- pressed in a wide range of cells and tissues, IL-34 is a specialized cy- are a large family of small secreted including tokine that show specific expression in the skin by keratinocytes, and , , , and tumor necrosis the brain by neurons at the resting state, and play critical roles in the factors. Cytokines are produced by a broad range of cells and mediate development and maintenance of Langerhans cells and microglia, re- autocrine and paracrine cell-, thus play critical roles in spectively [7–9]. Despite of its absence at the level, IL-34 can be communication between cells, tissues and organs in complex organ- detected at mRNA levels in various tissues and organs [1]. Importantly, isms. Through signaling via specific receptors, cytokines control major several reports have shown that IL-34 can be induced at both mRNA physiological functions at the cellular level (growth, proliferation and and protein levels in stressed cells, and this induction is regulated by migration), in addition to essential biological process such as in- NF-κB; the master regulator of inflammatory response [10,11]. This flammation, immunity and angiogenesis. Due to their critical functions, suggests the involvement of IL-34 in pathological conditions, and in- cytokines are involved in a wide variety of pathological conditions in- deed there is growing evidence that IL-34 contributes to the etiology of cluding inflammation, infection, autoimmunity and cancer. Thus, cy- various diseases including autoimmune disorders, infections, in- tokines have been considered as attractive therapeutic targets, diag- flammation and cancer. nostic tools and novel biomarkers that help to predict disease In this review, we summarize the current knowledge regarding the progression and severity. role of IL-34 in disease, with a special focus on the potential role of IL- (IL-34) is a hematopoietic cytokine that acts as a Key 34 as a novel diagnostic and prognostic biomarker of disease in medi- regulator of survival, proliferation and differentiation of myeloid cine. lineage cells including , macrophages and osteoclasts [1–3]. IL-34 was identified in 2008 as a second ligand of CSF1R, in addition to the previously well-known ligand, M-CSF [1]. IL-34 shares functional similarities with M-CSF, but also show different characteristics and

Abbreviations: anti-CCP, anti-cyclic citrullinated peptide antibody; BMI, body mass index; CCL20, CC ligand 20; C/EBPβ, CCAAT-enhancer-binding protein β; CRP, C-reactive protein; CSF1R, colony stimulating factor 1 receptor; DAS28, disease activity score 28; DMARDs, disease-modifying antirheumatic drug; eGFR, estimated glomerular filtration rate; ERK, extracellular-signal-regulated kinase; ESR, erythrocyte sedimentation rate; HOMA-IR, homeostasis model assessment for insulin resistance; hsCRP, high sensitivity C-reactive protein; IL- 1β, interleukin-1β; IL-6, interleukin-6; IL-17, interleukin-17; IL-23p19, interleukin-23p19; TJC, tender joint count; M-CSF, macrophage colony-stimulating factor; MMP-3, matrix me- talloproteinase 3; NF-κB, nuclear factor kappa B; RANKL, receptor activator of nuclear factor κB ligand; RF, rheumatoid factor; RYGB, Roux-en-Y bypass surgery; SAT, sc adipose tissue; TAT, total abdominal adipose tissue; TGFβ1, transforming β1; TLR, Toll-like receptor; TNFα, -α; VAT, visceral adipose tissue ⁎ Corresponding authors at: Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan. E-mail addresses: [email protected] (M. Baghdadi), [email protected] (K.-i. Seino). http://dx.doi.org/10.1016/j.cyto.2017.08.020 Received 28 June 2017; Received in revised form 7 August 2017; Accepted 25 August 2017 Available online 05 September 2017 1043-4666/ © 2017 Elsevier Ltd. All rights reserved. M. Baghdadi et al. Cytokine 99 (2017) 139–147

2. The role of IL-34 in autoimmune diseases critical role of monocytes in the expansion of inflammatory infiltrate in SS [24]. As a pro-inflammatory cytokine that affects monocytes 2.1. Rheumatoid arthritis biology, IL-34 may contribute to SS pathogenesis. In clinical samples, IL-34 was found to be highly expressed in the inflamed salivary glands Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune of primary Sjogren’s syndrome patients (p-SS) and correlated with in- disorder characterized by accumulation of inflammatory cells into the creased expression of pro-inflammatory cytokines such as TNFα, IL-1β, synovium resulting in joint destruction. Pro-inflammatory cytokines IL-17 and IL-23p19 [24]. Importantly, high expression of IL-34 is ac- play major roles in the regulation of synovial inflammation. The con- companied by the expansion of pro-inflammatory CD14brightCD16+ tribution of IL-34 in RA pathogenesis has been strongly suggested in monocytes in salivary glands; an observation supported by an evidence clinical studies [12–21]. IL-34 is produced by synovial fibroblasts in from in vitro studies where IL-34 stimulation of peripheral blood response to stimulation with pro-inflammatory cytokines such as TNFα mononuclear cells resulted in the expansion of CD14+CD16- and and IL-1β, and has a potential role in amplifying the inflammatory CD14brightCD16+ monocytes [24]. Together, IL-34 is suggested to play cascade [12–14]. IL-34 is released into synovial fluids (SF) of RA pa- important roles in the pathogenesis of salivary gland inflammation, and tients where it can be detected at high levels compared with osteoar- may serve as a biomarker to indicate disease severity, and a potential thritis patients (OA) or healthy controls [12–16]. A significant corre- therapeutic approach to p-SS treatment (Fig. 1). lation between SF IL-34 with disease parameters is observed in RA patients including histological severity of synovitis, synovial hyper- 2.4. Psoriasis and psoriatic arthritis plasia disease activity score, and inflammatory intensity as measured by leucocyte count and cytokine concentrations such as IL-6, TGFβ1 and Psoriasis (Ps) is a chronic autoimmune disease characterized by RANKL [12–16]. IL-34 can be also detected at high levels in the serum patches of abnormal skin. Chronic inflammation in Ps results in the of RA patients than OA or controls [13–17]. Similarly, serum IL-34 development of psoriatic arthritis (PsA) in 30% of Ps patients, which correlates positively with disease activity index (TJC and DAS28), in- frequently associates with progressive joint damage, osteoclastogenesis flammation parameters (ESR and CRP), auto-antibody production (RF and bone erosions. Pro-inflammatory cytokines such as TNFα, IL-1β and anti-CCP), and concentrations of other inflammatory mediators and IL-12 play important roles in the immunopathogenicity of Ps/PsA such as IL-6, IL-17 and MMP-3 [13–17]. Importantly, a significant de- by promoting systemic inflammation. The role of IL-34 in Ps/PsA has crease in serum IL-34 can be observed upon successful treatment with been recently suggested by the increased levels of serum IL-34 in Ps/ DMARDs or TNFα antagonist therapy [12–21]. Collectively, IL-34 is PsA patients than healthy controls, with remarkable higher levels in suggested to serve as a promising biomarker to assess radiographic PsA compared to Ps patients [25]. Furthermore, a range of bone progression and predict good response upon successful treatment in RA pathologies is observed in PsA patients, which are related to over-ac- patients, and additionally inhibition of IL-34 may provide a novel target tivated osteoclastogenesis [25]. In this context, serum IL-34 levels im- for therapies of RA (Fig. 1). portantly correlate with elevated numbers of circulating osteoclast precursors (OCPs), consistent with its critical roles in osteoclastogenesis 2.2. Systemic lupus erythematosus [25]. These initial findings indeed indicate an important role for IL-34 in the etiology of Ps/PsA, suggesting it as a potent biomarker to monitor Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease activity, and a potential therapeutic target to control in- disease, characterized by the development of anti-nuclear antibodies. flammation and bone erosion in Ps/PsA patients (Fig. 1). Although the exact etiology of SLE is still unclear, chronic inflammation mediated by anti-nuclear antibodies is implicated in the major com- 3. The role of IL-34 in metabolic diseases plications frequently observed in SLE patients. IL-34 was identified among a limited number of cytokines and chemokines that were in- 3.1. Obesity creased in of three independent mouse models of lupus ne- phritis, indicating a potential role of IL-34 in SLE pathogenesis [22]. Obesity is a leading preventable cause of death worldwide, with Consistent with this, serum IL-34 shows high levels in SLE patients increasing rates in adults and children. Obesity is a medical condition compared to healthy controls, and remarkably correlates with the ac- characterized by excess body fat and a state of low-grade chronic in- cumulation of SLE clinical features including malar rash/discoid rash, flammation associated with increased serum levels of pro-inflammatory alopecia, oral or nasal ulcers, serositis, arthritis, active nephritis, CNS cytokines and acute phase proteins. Chronic inflammation is involved lupus, vasculitis, fever, thrombocytopenia, leukopenia and anemia in the pathogenesis of obesity-associated complications such as insulin [23]. Moreover, serum IL-34 correlates positively with the systemic resistance and type II diabetes. Because of metabolic dysregulation and lupus erythematosus disease activity index, anti-double-stranded DNA cellular stress, adipocytes release several factors that recruit macro- antibody titers and CRP levels, but inversely with complement 3 [23]. phages into adipose tissues [26]. Adipose tissues-infiltrated macro- Importantly, serum IL-34 is significantly decreased after successful phages mediate chronicity and correlates positively with BMI [26].Asa treatment of SLE [23]. Together, serum IL-34 may serve as a helpful cytokine that dominates in chronic inflammation and affects macro- diagnostic and therapeutic biomarker for SLE, showing elevated levels phage biology, IL-34 is strongly suggested to have a role in the patho- in the serum of treatment-naive SLE patients, which are significantly genesis of obesity. Indeed, IL-34 expression can be detected in adipose decreased after effective treatment (Fig. 1). tissues, which is remarkably enhanced upon exposure to pro-in- flammatory cytokines such as TNFα and IL-1β [27]. Importantly, high 2.3. Sjogren’s syndrome levels of IL-34 can be observed in the serum of obese patients compared to controls (normal-weight healthy controls), which correlates posi- Sjogren’s syndrome (SS) is a systemic chronic autoimmune disease tively with insulin resistance-related metabolic parameters including characterized by a connective tissue disease associated with kerato- BMI, systolic BP, fasting plasma insulin, HOMA-IR, serum leptin, conjunctivitis sicca (dry eyes) or xerostomia (dry mouth), and usually hsCRP, TAT, VAT and SAT, with higher levels of IL-34 in VAT compared accompanies other autoimmune disorders such as rheumatoid arthritis to SAT [27]. Another interesting observation is that serum IL-34 is and lupus. A major feature of SS is the upregulation of pro-in- decreased after RYGB-induced weight loss [27]. Together, IL-34 is flammatory cytokines which results in enhanced infiltration of plasma suggested to play important roles in the pathogenesis of obesity and cells and lymphocytes into secretory glands leading to fibrosis and obesity-associated complications, suggesting IL-34 as a novel biomarker decreased secretory function. Several studies have emphasized the for diagnosis and therapeutic monitoring in obese patients (Fig. 1).

140 M. Baghdadi et al. Cytokine 99 (2017) 139–147

Fig. 1. The role of IL-34 in disease. IL-34 is a hematopoietic cytokine induced in inflammatory conditions and contribute of the etiology of several diseases. High expression of IL-34 correlates with disease severity and chronicity, such as in failure, fibrosis, kidney injuries, inflammatory bowel disease, rheumatoid arthritis, diabetes, Sjogren’s syndrome, systemic lupus erythematous and psoriasis. In contrast, decreased IL-34 expression correlates with disease severity in atopic dermatitis, resulting in developing lesional zones. In neurological diseases, IL-34 may play neuroprotective roles by limiting neuron cell death, promoting microglia proliferation and clearance of neurotoxins within the brain and main- taining the integrity of blood-brain barrier integrity.

3.2. Diabetes mellitus factors regulated by NF-κB and induced in inflammation, IL-34 may be similarly involved in HF. Depending on acuity and severity of signs and Diabetes mellitus is a chronic metabolic disorder characterized by symptoms, HF can be classified into acute heart failure (AHF) and hyperglycemia resulting from a lack, diminished or developed re- chronic heart failure (CHF). Coronary artery disease (CAD) is the most sistance to endogenous insulin. As described above, serum IL-34 is frequent cause of AHF, resulting in high mortality in the United States significantly elevated in obese patients and positively correlates with and worldwide in both men and women. In CAD, serum levels of hsCRP, insulin resistance-related metabolic parameters [27]. IL-34 was iden- a protein synthesized by the liver in response to acute inflammatory tified within risk loci for type II diabetes in a population of Mexican- conditions, are increased during the atherosclerotic process, and serve American patients using genome-wide association studies (GWASs) and as a biomarker for cardiovascular risk prediction. In addition to hsCRP, expression quantitative trait loci (eQTL) analysis [28]. Additionally, IL- serum IL-34 can be found at high levels in CAD patients (identified with 34 is located at 16q22.1 and serves as a risk factor for diabetic ne- coronary artery stenosis ≥50%) compared with control group (cor- phropathy in a Han Chinese population [29]. In consistent with these onary artery stenosis < 50%), and a significant positive correlation studies, serum IL-34 show high levels in patients with type II diabetes between IL-34 and hsCRP is observed in CAD patients, importantly mellitus (T2DM) compared to controls, and the receiver operating suggesting that IL-34 may serve as an independent predictor of AHF characteristic curve analysis showed that IL-34 has more discriminatory [31]. Upon progression toward chronicity, HF is frequently associated power than CRP for the risk of diabetic complications [30], suggesting with serious complications such as coronary artery lesions and renal that IL-34 may serve as an additional potential inflammatory biomarker dysfunction. In CHF patients, serum IL-34 correlates with the presence to predict the risks of diabetes and diabetic complications (Fig. 1). and severity of renal dysfunction as evaluated by eGFR, creatinine and cystatin C on multivariable linear and logistic regression analysis [32]. 4. The role of IL-34 in cardiovascular diseases As in AHF, serum IL-34 correlates positively with hsCRP in CHF patients [32], indicating a possible role for IL-34 as an independent predictor of Heart failure (HF) is a clinical syndrome occurs when cardiac output severity and prognosis in both AHF and CHF, and may provide new and blood pressure are insufficient for the body’s requirements. In ad- insights that link kidney impairment to poor HF outcomes beyond other – dition to atherosclerosis, inflammation and inflammation-induced pro- renal markers [31 33] (Fig. 1). inflammatory cytokines such as TNFα, IL-6 and IL-18 play critical roles in HF initiation and progression, thus may provide critical information for diagnosis and therapeutic monitoring in HF patients [31]. As one of

141 M. Baghdadi et al. Cytokine 99 (2017) 139–147

5. The role of IL-34 in liver diseases normal tissues, which is similarly confirmed in experimental colitis in mice [39,40]. IL-34 expression can be induced in normal lamina propria Non-alcoholic fatty liver disease (NAFLD) is a common disorder mononuclear cells (LPMCs) by pro-inflammatory factors such as TNFα characterized by accumulation of excess fat in the liver of non-alcoholic and TLR ligands via NF-κB pathway [39,40]. Interestingly, treatment of individuals, which consequently results in chronic liver disease. In normal LPMCs with IL-34 enhances the expression of pro-inflammatory NAFLD, macrophages and hepatic stellate cells are chronically activated cytokines such as TNFα and IL-6 and chemokines like CCL20 in an and mediate liver fibrosis; a major clinical feature of NAFLD which has ERK1/2-dependent manner, suggesting an important role for IL-34- significant impact on prognosis of NAFLD patient. Accordingly, de- mediated positive autocrine loop in amplifying the destructive immune termining of fibrosis stage is critical for NAFLD management, which can inflammatory response in IBD patients [39–41]. Consistent with this, be evaluated efficiently by chronic inflammation-induced factors. In treatment of intestinal biopsies and LPMCs of IBD patients with neu- liver specimens obtained from NAFLD patients, IL-34 was found to be tralizing antibodies of TNFα results in decreased IL-34 expression, and highly expressed by liver fibroblasts [34]. Serum IL-34 shows high le- TNFα expression in turn is also decreased in IBD mucosal explants when vels in NAFLD patients compared to healthy volunteers, and correlated treated with neutralizing antibodies of IL-34 [39,40]. Collectively, IL- with the progression of fibrosis [34]. Using receiver-operating char- 34 may serve as a novel biomarker to evaluate IBD severity, and a acteristic analyses, the sensitivity and specificity of IL-34-based fibrosis potential therapeutic target to attenuate inflammation in IBD patients score were superior or comparable to other fibrosis biomarkers and (Fig. 1). scores, suggesting IL-34 as a feasible diagnostic marker of liver fibrosis in NAFLD patients (Fig. 1). 8. The role of IL-34 in skin diseases

6. The role of IL-34 in kidney injuries IL-34 is a unique cytokine which functions predominately in the epidermis of the skin, where it plays critical roles in the differentiation, Acute kidney injury (AKI) is a sudden and significant failure in renal proliferation and maintenance of Langerhans cells during steady states. function that develops within 7 days. AKI occurs due to damage in Accordingly, IL-34 abnormalities are expected to play major roles in the kidney tissues caused by kidney ischemia, exposure to harmful sub- pathogenesis of skin diseases. Atopic dermatitis (AD) is one of the major stances, or obstructions of the urinary tract. Inflammation is a major forms of skin diseases, characterized by a chronic eruption of pruritic, clinical feature of AKI, which is regulated mainly by macrophages. erythematous, oozing papules and plaques. Inflammatory lesions are Macrophages play dual roles in AKI; they may resolve the inflammatory also frequently observed in AD. Although the etiology of AD is still response, or alternatively leads to chronic Kidney disease (CKD) unclear, cellular and molecular components of the skin have been [35,36]. Since macrophages mediate kidney repair and destruction, suggested to play key roles in AD pathogenicity. In a genomic profiling molecules that control macrophages survival, proliferation and activa- of the epidermal and dermal components of lesional (LS) and non-le- tion are expected to be critical for determining the fate of kidney. sional (NL) AD, IL-34 expression was found to be significantly de- Previous studies suggest a positive role for M-CSF in AKI, which is creased in LS AD compared to NL AD and normal epidermis [42]. This beneficial for kidney repair [37]. On the other hand, IL-34 expression is interesting finding indicates the importance of IL-34 in skin home- accompanied with severe AKI and worsening the subsequent CKD [38]. ostasis, suggesting it as a negative regulator of inflammation in LS AD, In a mouse model of I/R, IL-34 is upregulated in tubular epithelial cells and on the opposite, its induction in NL skin may help to suppress in- (TECs) during the acute phase and remains elevated during the chronic flammation and prevent the development of active skin lesions (Fig. 1). phase after I/R, showing maximum expression in the most sensitive site to I/R injury; the medulla [38]. Functionally, IL-34 enhances local 9. The role of IL-34 in neurological diseases proliferation of macrophages that mediate TEC destruction. After re- leasing into circulation, IL-34 induces proliferation of myeloid cell In the central nervous system (CNS), IL-34 is primarily produced by lineage in the bone marrow, thus enriches the circulation with a large neurons, where it plays important roles in CNS development and pool of myeloid cells, which are consequently recruited by IL-34-in- function [43,44]. In particular, IL-34 has critical roles in the main- duced chemokines at the inflamed kidney [38]. Similar findings can tenance of CNS homeostasis by acting on various cell types including also be observed in engrafted and rejected kidney after transplantation neurons, microglia and endothelial cells [43–50]. In primary neurons, in patients, since I/R injury is an inevitable consequence of kidney IL-34 induces activation of p-CREB signaling pathway via CSF1R, which transplant, and prolonged ischemia results in poor graft survival [38]. promotes neuron survival and protection against neurotoxins [49]. Via IL-34 is upregulated in the engrafted kidney compared with donor the same receptor, IL-34 also enhances microglial proliferation and kidney, and shows increased expression during acute kidney rejection neuro-protective functions to attenuate Oligomeric Amyloid-β neuro- [38]. TECs are the cellular resource of IL-34, which in turn increases toxicity through up-regulation of Insulin-Degrading Enzyme (IDE) and frequencies of CD68+ macrophages and Ly6G+ neutrophils in the en- Heme Oxygenase-1 (HO-1) [46,47]. CNS capillary endothelial cells also grafted kidney [38]. Consistent with this, serum IL-34 show high levels express CSF1R, and response to IL-34 by up-regulating several tight in patients compared to healthy controls and correlates with poorer junctions molecules, indicating a critical role for IL-34 in the main- survival of transplanted kidney [38]. Together, IL-34 is suggested to tenance of the blood-brain barrier (BBB) integrity [48]. From these play critical roles in kidney injuries and rejection of transplanted backgrounds, IL-34 is expected to play major roles in the pathology of kidney, suggesting it as a potential biomarker to monitor disease pro- several neurological disorders. IL-34 is enhanced in damaged gression and a therapeutic target to inhibit AKI and the subsequent CKD neurons, and mediates neuronal rescue by autocrine activation of sur- (Fig. 1). vival pathways in damaged neurons, in addition to paracrine effects on microglia, promoting microglial proliferation and neuro-protective 7. The role of IL-34 in inflammatory bowel disease functions represented by phagocytosis of toxicants and damaged debris, and productions of anti-oxidant enzymes [46,47,49]. The blood-brain Inflammatory bowel disease (IBD) is a chronic inflammatory dis- barrier disruption is a common pathological feature in various neuro- order of the colonic mucosa, characterized by relapses and remissions. logical diseases, which is induced by pro-inflammatory cytokines such Crohn’s disease (CD) and ulcerative colitis (UC) represent the two major as IL-1β and TNFα [48]. IL-34 can help effectively to restore BBB in- forms of IBD. The role of IL-34 in IBD has been evaluated in experi- tegrity by up-regulating tight junction molecules in BBB endothelial mental animal models and IBD patients. Clinically, IL-34 show high cells [48]. The importance of IL-34 in neurological diseases has been expression in inflamed mucosa of CD and UC patients compared with also unveiled using several experimental models. IL-34-deficient mice

142 M. Baghdadi et al. Cytokine 99 (2017) 139–147 showed remarkable decrease in microglia cell numbers [7–9], which virus (IAV), IL-34 expression is induced by IL-22 inflammatory cascade consequently resulted in significantly augmented proteinase K-resistant in IAV-infected peripheral blood mononuclear cells (PBMCs), which prion protein deposition and accelerated prion disease progression results in high levels of serum IL-34 in IAV-infected patients compared [50]. On the other hand, systemic administration of IL-34 in mice to healthy individuals. Blocking of IL-22 signaling cascade results in a strongly reduced excitotoxin-induced neuronal loss and gliosis [49]. significant decrease in IL-34 expression, which collectively suggest IL- Similarly, intracerebroventicular administration of IL-34 ameliorated 34 as a promising biomarker for monitoring of disease progression and impairment of associative learning and reduced αAβ levels in an APP/ screening of anti-inflammatory medicine in viral infections [52] PS1 transgenic mouse model of AD [46]. Together, IL-34 is suggested to (Fig. 2). In addition to HCV and IAV, IL-34 is suggested to play critical provide powerful neuro-protective and survival signals in brain injury roles in the etiology of equine infectious anemia virus (EIAV). S2, a and neuro-degeneration, and thus may help as a useful therapeutic viral protein that correlates with viral replication, induces IL-34 ex- approach for the treatment of neurological diseases including AD pression in EIAV-infected macrophages, which in turn promotes the (Fig. 1). proliferation of /macrophage lineage cells in bone marrow. Monocyte/macrophage lineage cells are the natural targets of EIAV, 10. The role of IL-34 in infectious diseases thus IL-34 may help to promote a suitable cellular environment that is likely to promote viral replication [53] (Fig. 2). EIAV is a virus closely Cytokines play critical roles in initiating innate immunity against related to human immunodeficiency virus (HIV) [53]. Accordingly, IL- infectious agents, and regulating the following adaptive immune re- 34 may also have a potential role in HIV [54] pathogenesis. This is sponse. On the other hand, cytokines may also contribute to the pa- supported by evidence from in vitro study. Replication of HIV1 viruses thogenesis of infections. The role of IL-34 in infections has been eval- showed tendency to be higher in macrophages stimulated with IL-34 uated in viral infections including hepatitis and influenza. In chronic compared to M-CSF, which was the result of strongly activated MAPK hepatitis C virus (HCV) infections, IL-34 is produced by hepatocytes in pathway by IL-34 [4]. chronically injured liver, and mediates accumulation and differentia- On the contrary, IL-34 may also play important roles in antiviral tion of monocytes into profibrotic macrophages, resulting in pro- immunity. For example, in hepatitis B virus (HBV) infections, serum IL- gressive hepatic fibrosis. Consistent with this, serum IL-34 is elevated in 34 in chronic HBV patients shows decreased levels compared to healthy HCV-infected patients, and correlates positively with advanced liver controls, and IL-34 mRNA levels in peripheral blood mononuclear cells fibrosis, similar with NAFLD [51] (Fig. 2). In infections with influenza A (PBMCs) in chronic HBV patients are also decreased relative to healthy

Fig. 2. The role of IL-34 in infection. IL-34 expression is induced in various viral infections such as HCV, HBV, IAV and EIAV. In HCV infection, IL-34 is produced by infected hepatocytes and mediates formation of fibroblastic macrophages resulting in liver fibrosis. In contrast, IL-34 expression is decreased in HBV patients and HBV-infected cells, and IL-34 can effectively inhibit HBV replication in vitro and in vivo. IAV-infected PBMCs produce IL-34, which modulate inflammatory cascades during infection. In EIAV infection, EIAV-infected macrophages secrete IL-34 that enhances proliferation of the myeloid cell lineage in bone marrow, thus enriches the circulation with natural targets of EIAV for viral infection and replication.

143 M. Baghdadi et al. Cytokine 99 (2017) 139–147 controls [55]. These findings indicate a negative relation between HBV functions via autocrine and paracrine pathways to promote tumor and IL-34, which is supported by evidence from in vitro experiments. In progression. In the autocrine pathway, IL-34 acts on CSF1R-expressing HBV-infected cells, high HBV copy number is associated with decreased cancer cells, leading to activation of AKT signaling pathway, thus help levels of secreted IL-34, while on the other hand; stimulation of HBV- to overcome strict conditions such as chemotherapy in cancers and infected cells with IL-34 significantly inhibits HBV replication [55]. malignant pleural mesothelioma [61,64] (Fig. 3). In the paracrine This is also supported by experimental animal model and clinical evi- pathway, IL-34 promotes the recruitment of M2-polarized tumor-asso- dence. Serum IL-34 negatively correlates with serum level of HBV DNA, ciated macrophages (TAMs) by a direct effect on CSF1R signaling in and importantly with liver injury markers such as ALT and AST in macrophages in addition to promoting new vessel formation and ex- chronic HBV patients [55]. Thus, in HBV infections IL-34 may serve as a travasation of immune cells [60]. After recruitment into the TME, IL-34 biomarker to monitor HBV infection and estimate liver damage, and affects TAMs functions in different ways (Fig. 3). IL-34 induces strong also a therapeutic tool that may benefit to inhibit HBV replication in phosphorylation of CSF1R in TAMs, which in turn leads to activation of patients [55]. C/EBPβ via AKT-mediated pathway. The activation of C/EBPβ cascade Added to viral infections, IL-34 is also suggested to be involved in enhances the pro-tumorigenic and immunosuppressive functions of T- parasitic diseases, such as parasitic proliferative kidney disease (PKD) AMs, which consequently contribute to therapeutic resistance in lung in teleost fish [56] and cryptocaryon irritans in grouper [57]. Thus, IL- cancers [61]. IL-34 also mediates interaction between cancer cells and 34 is expected to play novel roles in infections, serving as a biomarker TAMs. In hepatocellular carcinoma (HCC), IL-34 is produced by HCC that help to evaluate disease progression and chronicity, and a potential cells and enhances TGFβ expression in TAMs. TAMs-derived TGFβ en- therapeutic target for controlling infections, which should be clarified hances IL-34 production in HCC cells by decreasing miR-28-5p, one of in future studies. the microRNAs that suppress IL-34 expression in HCC cells. The re- sulting IL-34-TAMs-TGFβ positive feedback loop mediates tumor pro- 11. The role of IL-34 in transplantation gression and metastasis of HCC [65]. Additionally, IL-34 plays im- portant roles in fueling stemness of cancer cells. In cholangiocarcinoma, In transplantation, graft rejection due to allogenic immune re- IL-34 is produced by cancer stem cells (CSCs) among other factors, sponses remains a critical issue within the transplant community, and it which together induce macrophage infiltration, differentiation and ac- is obviously important to monitor and manage graft health during the tivation towards acquisition of CSC-associated macrophages phenotype, postoperative period. In this regard, the role of IL-34 in transplantation thus promoting stemness features in CSCs [66]. has been evaluated in transplant patients and experimental animal The expression of IL-34 in cancer is supported by integrative models. In kidney transplantation, Il-34 is induced in TECs within the genomic analysis that indeed identified the expression of IL-34 in var- engrafted kidney and mediates proliferation of graft-infiltrating mac- ious cancers including blood, brain, breast, colorectal, eye, head and rophages and neutrophils [58]. Upon release into circulation, IL-34 neck, lung and ovarian cancer [67]. However, the molecular mechan- shows high levels in patients compared to healthy controls, and cor- isms that control IL-34 in cancer cells remain unknown. Oncogenic relates with poorer survival of transplanted kidney [58]. Consistent mutations frequently activate a constellation of signaling resulting in with these findings, serum IL-34 is significantly elevated during acute over-expression of cytokines and chemokines that promote tumor- rejection in human liver transplant recipients. The concentrations of igenesis. Future studies on the possible relation between oncogenic serum IL-34 are higher in patients after liver transplantation compared mutations and IL-34 expression in cancer cells will certainly help to to healthy controls, and shows higher levels in the rejection group give new insights into the role of IL-34 in cancer, and provide new compared to non-rejection group during the entire postoperative therapeutic targets to specifically inhibit signaling pathways that con- period. Thus, IL-34 may serve as a powerful biomarker to monitor the trol IL-34 production in cancer cells. allogenic inflammatory response in kidney and liver transplantation In addition to the protumorigenic functions described above, IL-34 [58]. On the other hand, IL-34 may also mediate transplant tolerance. may exhibit unique functions in different conditions. For example, IL- In a rat model of heart transplantation, IL-34 serves as a specific cy- 34 inhibits proliferation, clonogenecity and motility of glioblastoma tokine produced by regulatory T cells (Treg) that inhibit alloreactive cell lines such as U251 via PTPRZ1 [68], and induces the differentiation immune responses and thus enhancing transplant tolerance and pro- of monoblastic leukemia cells into monocyte-like cells via CSF1R [69]. longation of graft survival [59]. IL-34 induces monocytes differentia- Additionally, IL-34 promotes migration of myeloid cells in a Syndecan- tion into macrophages with immune-modulatory functions, which in 1-depedent manner [70]. These findings raise two important issues. turn induce Treg expansion and potentiation resulting in central tol- First, IL-34 may act directly on cancer cells, which will depend on re- erance [59]. Collectively, these studies show induced expression of IL- ceptors and/or regulators expressed in cancer cells. This may indeed 34 after transplantation; however, the role of IL-34 in transplant tol- explain why low expression of IL-34 correlates with poor prognosis in erance is controversial and may depend on the organ and micro- some cases of lung, blood and colorectal cancers [67]. Second, IL-34 environment, which should be addressed in future studies. binds to several receptors including CSF1R, Syndecan-1 and PTPRZ1, which are frequently expressed in various cancers. Consequently, in- 12. The role of IL-34 in cancer hibition of CSF1R signaling alone is expected to be insufficient to completely block IL-34 signaling in tumors, and targeting of IL-34 may Upon malignant transformation, cancer cells produce a variety of be critical for effective cancer therapy in IL-34-producing cancers, cytokines and chemokines that help to establish a microenvironment which is under investigation in our current work. In conclusion, IL-34 favorable for tumor progression. IL-34 is expressed in various cancers may serve as a critical prognostic biomarker and a therapeutic target of and play important roles in multiple aspects of the tumor micro- great potential in cancer treatment. environment (TME) (Fig. 3). IL-34 expression correlates with tumor progression as observed in osteosarcoma and lung cancer [60,61], 13. Concluding remarks metastasis in osteosarcoma and breast cancer [60,62], angiogenesis in osteosarcoma [60], and a potential involvement in GCTs-induced os- Despite of its recent discovery, there is growing evidence that IL-34 teoclastogenesis [63]. Importantly, IL-34 expression is induced in play important roles in health and disease. IL-34 was identified as a cancer cells under therapeutic conditions such as chemotherapy, and cytokine that selectively enhances monocyte viability. In a search for can be detected at high levels in cells rendered resistant to che- IL-34 receptors, IL-34 was found to interact with the extracellular do- motherapeutic agents [61]. Thus, the expression of IL-34 in tumors may main (ECD) of CSF1R, and induces activation of downstream signaling help as a biomarker that correlates with malignancy. At the TME, IL-34 pathways [1]. Thus, as a second ligand of CSF1R, IL-34 is expected to be

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Fig. 3. The role of IL-34 in cancer. Cancer cells-derived IL-34 plays critical roles in multiple aspect of TME including tumor growth, angiogenesis, invasion, metastasis and osteoclas- togenesis. IL-34 has autocrine effects on cancer cells, represented by activation of AKT signaling pathway in CSF1R-expressing cancer cells, thus contributes to cell survival and consequently therapeutic resistance. IL-34 expression in cancer correlates with enrichment of TME with M2-polarized macrophages with enhanced functions, promoting tumorigenesis, immunosuppression and cancer cell stemness. involved in all aspects of myeloid cells biology, such as proliferation, points of IL-34 is its tissue-specific expression patterns. Under physio- survival, migration and differentiation [71–73]. However, in addition logical conditions, IL-34 expression is restricted to the epidermis and to CSF1R, 10 of 858 ECDs tested in the screening of IL-34 receptors CNS [7–9]. When it is expressed where it should not, IL-34 indicates an could inhibit IL-34 activity, although CSF1R is the only one that showed acute inflammatory response with a tendency towards chronicity. On reproducible inhibition in repeated testing [1]. This indicates that IL-34 the opposite, decreased IL-34 expression affects the homeostatic status may interact with other receptors in addition to CSF1R. Indeed, IL-34 in skin and probably in CNS, indicating different roles of IL-34 in dis- was found later to bind to Syndecan-1, and this binding modulates IL- ease pathogenesis. Clinically, IL-34 may serve as a novel biomarker and 34-induced CSF1R activation and affects cellular migration [70]. Fur- prognostic predictor in various medical fields including autoimmune thermore, IL-34 binds to PTPRZ1 and negatively control proliferation, disorders, inflammatory diseases, infections, transplantation and clonogenecity and motility of glioma cells [68]. Future studies may also cancer. Additionally, IL-34 may also serve as a promising therapeutic identify additional receptors and/or regulators that control the biologic target of great potential. Studies on knockout mice showed that mice activities of IL-34. While this may complicate the understanding of IL- defective in CSF1R or M-CSF exhibit severe osteopetrosis and systemic 34 biology, it will certainly help to explain the controversial effects of depletion of myeloid cell lineage, with a stronger phenotype in CSF1R- IL-34 on immune responses and its immuno-regulatory functions in deficient compared to M-CSF-deficient mice [71]. In contrast, IL-34- health and disease. For example, PTPRZ1 and CSF1R show different deficient mice showed decreased frequencies of Langerhans cells and expression patterns in colon tissues. High expression of PTPRZ1 can be microglia, which did not develop into visible symptoms [7–9]. Thus, observed in the epithelium, but not in immune cells. On the contrast, targeting of IL-34 in disease may serve as an ideal strategy to minimize CSF1R expression can be highly detected in PBMCs, monocytes, mac- side effects and maximize clinical responses [75], which should be rophages, and interestingly in some intestinal epithelial cell lines [74]. elucidated in future studies. Thus, both immune and epithelial cells will response to IL-34 but via different receptors. In inflammatory conditions such as IBD, the altered Acknowledgements expression of these receptors will have impact on the activities of in- flammation-induced IL-34 and consequently on disease progression. This work was supported in part by Japan Agency for Medical This also applies to various pathological conditions, which should be Research and Development (AMED; Practical Research for Innovative clarified in future studies. Cancer Control) (K. Seino). Figures were produced using Servier As a biomarker and therapeutic target, one of the most attractive Medical Art.

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