Cell. Mol. Life Sci. (2017) 74:2569–2586 DOI 10.1007/s00018-017-2482-4 Cellular and Molecular LifeSciences REVIEW Immunoregulatory properties of the cytokine IL-34 Carole Guillonneau1,2 · Séverine Bézie1,2 · Ignacio Anegon1,2 Received: 22 November 2016 / Revised: 10 January 2017 / Accepted: 30 January 2017 / Published online: 3 March 2017 © Springer International Publishing 2017 Abstract Interleukin-34 is a cytokine with only partially Introduction understood functions, described for the frst time in 2008. Although IL-34 shares very little homology with CSF-1 The CSF-1/CSF-1R interaction delivers a well-character- (CSF1, M-CSF), they share a common receptor CSF-1R ized signaling cascade leading in hematopoietic cells to (CSF-1R) and IL-34 has also two distinct receptors (PTP-ζ) proliferation, diferentiation, and function of the mono- and CD138 (syndecan-1). To make the situation more com- cytic lineage. The discovery in 2008 of IL-34, identifed by plex, IL-34 has also been shown as pairing with CSF-1 to screening of human protein library as a protein involved in form a heterodimer. Until now, studies have demonstrated monocyte viability [1] and subsequently, as a new ligand that this cytokine is released by some tissues that difer to of CSF-1R, has opened new perspectives. IL-34 actions those where CSF-1 is expressed and is involved in the dif- have been rendered more complex by the discovery of ferentiation and survival of macrophages, monocytes, and receptors for IL-34, others than CSF-1R: the receptor-type dendritic cells in response to infammation. The involve- protein-tyrosine phosphatase zeta (PTP-ζ), identifed only ment of IL-34 has been shown in areas as diverse as neu- in the brain and in the kidney [2, 3], and syndecan-1, with ronal protection, autoimmune diseases, infection, cancer, a broad distribution [4], altogether suggesting additional and transplantation. Our recent work has demonstrated a roles for IL-34. IL-34 is a 241 amino acid (aa) protein in new and possible therapeutic role for IL-34 as a Foxp3 + humans that were originally characterized as a protein Treg-secreted cytokine mediator of transplant tolerance. In with no evident sequence similarity with other cytokines this review, we recapitulate most recent fndings on IL-34 or proteins (26% sequence homology with CSF-1). IL-34 and its controversial efects on immune responses and exists in two isoforms, difering by the addition of a glu- address its immunoregulatory properties and the potential tamine inserted between position 80 and 81 in the 241 aa of targeting this cytokine in human. isoform, and generated by alternative splicing [5]. IL-34 is formed by four α-helix and disulfdes bond that lead to Keywords Immune tolerance · Tregs · Ischemia the formation of a homodimeric protein, but the existence reperfusion · Macrophages · Osteopetrosis · CSF-1(M- also of a heterodimeric protein between IL-34 and CSF-1, CSF) inducing a diferent signaling cascade in CSF-1R recep- tor, has been described, although the physiopathological signifcance of this discovery remains unclear [6]. Finally, IL-34 is a cytokine relatively conserved between species * Carole Guillonneau with 99.6% homology between human and chimpanzee and [email protected] 72% between human, rat, or mouse [1]. Since 2008, stud- 1 INSERM UMR1064, Center for Research in Transplantation ies have identifed roles for IL-34 in areas as remote as and Immunology-ITUN, Université de Nantes, 30 Bd. Jean neuronal protection, bone-degenerative diseases, delayed- Monnet, 44093 Nantes Cedex 01, France type hypersensitivity, infection, cancer, and more recently 2 Institut de Transplantation Urologie Néphrologie (ITUN), transplantation. CHU Nantes, Nantes, France Vol.:(0123456789)1 3 2570 C. Guillonneau et al. Here, we summarize recent fnding on IL-34 biology, Inhibition of CSF-1R has shown its involvement in pro- signaling, and downstream efects and discuss in particular liferation and kidney graft infltration by macrophages [25] its controversial efect on immunity vs. immune tolerance and its potential in reducing macrophages proliferation (Table 1). and associated pathology in infammatory arthritis [26] and myelin oligodendrocyte glycoprotein (MOG)-induced EAE in mice [27]. CSF-1R is also involved in induction of regulatory macrophages and it has been demonstrated that IL-34, a cytokine with a complex biology, which CSF-1R blockade using antibodies reduced resident tumor- is a lot more than a substitute of CSF-1 associated macrophages (TAM) number in tumors [28] and exacerbate graft-versus-host disease (GVHD) following Until recently, IL-34 was described as expressed in spleen, bone-marrow transplantation in mice [29]. thymus, heart, brain, lung, liver, kidney, testis, prostate, CSF-1 ligation to CSF-1R is only based on saline bonds, ovary, small intestine, and colon [1]. Additional and more while IL-34 ligation to CSF-1R needs hydrophobic amino detailed expression has been described in “osteoclasts-like” acids and hydrogen bonds, suggesting a rather specifc bone giant cell tumors, osteoblasts but not osteoclasts [7], structure and chemical constraints supporting a co-evolu- keratinocytes, hair follicles, proximal kidney cells, germ tion of CSF-1R with IL-34 rather than CSF-1 [10]. How- cells, neurons in the brain (cortex, hippocampus) as well ever, afnity of IL-34 for the receptor CSF-1R is stronger as in the cerebrospinal fuid [8]. A weak expression of the than CSF-1 for CSF-1R; indeed, IL-34 recruits two protein in the spleen, especially in the red pulp, was also domains of CSF-1R, while CSF-1 recruits only one [1, 30]. reported [1, 8]. Finally, expression in fbroblasts and syn- Signal transduction through CSF-1R after ligation by IL-34 oviocytes from patients with rheumatoid arthritis has been involves a stronger but shorter phosphorylation of ERK1/2 described [9]. IL-34 and CSF-1 have partially non-over- and AKT than CSF-1 and decreases CSF-1R expression, lapping expression. IL-34 but not CSF-1 is expressed by leading to diferentiated macrophages with distinct mor- keratynocytes and neurons, whereas both cytokines share phology (few aggregates vs. many large aggregates with several other cellular sources [10] (Fig. 1). CSF-1) and phenotype (less CD54 expression and mono- IL-34 shares some partially overlapping actions with cyte chemoattractant protein-1 (MCP-1/CCL2) production, CSF-1, such as its efect on macrophages and neurons more HLA-DR expression, and eotaxin-2 production) [31]. (Fig. 1). The CSF-1R is encoded by a proto-oncogen and In addition, it has been reported that IL-34 and CSF-1 have has a tyrosine kinase activity, and ligation of CSF-1R diferent levels of expression in diferent organs. induces the phosphorylation of a tyrosine residue of the Since IL-34 acts through the same receptor as CSF- CSF-1R cytoplasmic domain and its homodimerisation, 1, therapies directed to block CSF-1R could be viewed as and initiates a cascade of phosphorylation of other proteins, sufcient to neutralize the efects of IL-34; however, more such as ERK1/2 (extracellular signal-regulated kinase) recently, it has been described that IL-34 binds to other or AKT (protein kinase B) [11–13]. CSF-1R is expressed receptors through low afnity interactions with chondroi- by dendritic cells (DCs) and macrophages, excluding tin sulphate chains, such as PTP-ζ [2] and syndecan-1 [4]. CD11c+ precursors of DCs. However, its expression has Thus, blocking of CSF-1R is not expected to inhibit the been described in CD11c dimB220+ plasmacytoid DCs using actions of IL-34 through these other receptors but blockade green fuorescent protein (GFP) transgenic mice (with GFP of these receptors and not of CSF1-R has not been reported under control of CSF-1R promoter), in Langerhans cells, yet. PTP-ζ is expressed as a cell surface or as a soluble B cells, smooth muscle cells of the vessels, osteoclasts as receptor by neural progenitors, glia, glioblastoma, B cells, well as trophoblast cell lineages, and to some extent granu- and kidney tubular cells [2, 3, 32]. Activation of PTP- locytes [14–20]. CSF-1R defcient mice and CSF-1-def- ζ leads to increased tyrosine phosphorylation of several cient rat toothless/toothless (tl/tl) both present a defect in transduction pathways and is upregulated in many human macrophages, osteopetrosis, are toothless, and have growth cancers (such as lung and prostate cancers) in chronic oxi- retardation, low fertility, and skeletal defects, which cannot dative stress in kidney cells and regulates their prolifera- be compensated by CSF-1 administration [21, 22]. CSF-1R tion and metastasis [3, 33–37]. PTP-ζ has other ligands, gene polymorphism has been demonstrated as a suscepti- such as pleiotrophin [38], the cell surface protein contactin bility marker of asthma with higher frequencies of two [39], and the extracellular matrix protein tenascin-R [40]. intronic polymorphisms and higher expression of CSF-1R The role of IL-34 binding on PTP-ζ remains unexplored. on CD14+ monocytes and neutrophils in asthmatic subjects IL-34 binding to syndecan-1 modulates the IL-34-induced than in normal controls [23]. CSF-1R gene expression was CSF-1R signaling pathways, and IL-34 induced the migra- increased in infammatory bowel disease (IBD) patients tion of myeloid cells in a syndecan-1-dependent manner with colon cancer than in active chronic IBD [24]. [4]. Syndecan-1 is expressed by many cancers [41], like 1 3 Immunoregulatory properties of the cytokine IL-34 Table 1 Biological and pathophysiological studies