Interleukin-34: Regulator of T Lymphocytes in Rheumatoid Arthritis

Interleukin-34 (IL-34) is a pleiotropic cytokine, which is implicated in various autoimmune diseases. Interestingly, clinical studies have found that IL-34 is markedly upregulated in the serum and synovium of patients with rheumatoid arthritis (RA), giving rise to a growing interest in understanding the role of IL-34 in RA. Although several studies demonstrated that IL-34 levels closely correlate with the disease severity, the function of circulating and synovial IL-34 in RA is still largely elusive. IL-34 was originally identified as a ligand of the colony-stimulating factor-1 receptor (CSF-1R), which is crucial for the survival, proliferation, and differentiation of mononuclear phagocytes (e.g. monocytes, macrophages [M] and dendritic cells [DC]). Of note, these IL-34-responsive cells are antigen-presenting cells, which bridge innate and adaptive immunity (e.g. through priming and instructing T lymphocytes). Thus, synovial IL-34 expression has been associated with the regulation of synovial M and linked to pathologic T-cell activation in RA. In this review, we discuss the current state of knowledge on the role of IL-34 in RA and, especially, focus on the impact of IL-34 on T lymphocyte activation in RA based on findings from translational and clinical studies.


Introduction
Rheumatoid Arthritis (RA) is a common inflammatory autoimmune disease with complex etiologies, which primarily affects joints. RA is primarily caused by self-reactive immune responses and involves a variety of immune cells, including (1) innate immune cells (e.g. macrophages (M) and neutrophils), which are the first responders in inflammation; and (2) adaptive immune cells (e.g. B and T lymphocytes), which trigger highly effective secondary immune responses targeting specific antigens.
M, neutrophils, and effector T lymphocytes (Teff) are prominent immune cells in the synovium of RA patients [1]. Interestingly, several alleles of human leukocyte antigen (HLA) class II histocompatibility antigen, DRB1 beta chain (encoded by HLA-DRB1) have been highly associated with increased incidence of RA and higher inflammatory activity in early RA [2][3][4][5], indicating that the interaction between antigen-presenting cells and T lymphocytes followed by an aberrant T-cell activation is a key mechanism in the pathogenesis of RA.
of IL-34 have been described, the immunological role of IL-34 is still under debate, as IL-34 can be both pro-and anti-inflammatory depending on the clinical setting [16][17][18][19][20][21]. Notably, several studies have proposed a role of IL-34 in the regulation of T lymphocytes in RA. In this review, we discuss the current state of knowledge of the role of IL-34 in RA and, especially, focus on the impact of IL-34 on T-cell regulation in RA.

IL-34 In RA
IL-34 is a ligand for the colony-stimulating factor-1 receptor (CSF-1R), which is essential for the maintenance of mononuclear phagocytes, including monocytes, M, DC in tissue homeostasis and inflammation [22,23]. Studies have identified fibroblast-like synoviocytes (FLS) as a source for IL-34. IL-34 was found to be produced by FLS upon stimulation with tumor necrosis factoralpha (TNF-) in vitro [10]. CSF-1R has another ligand, which is colony-stimulating factor-1 (CSF-1; also known as M-CSF). Although IL-34 and CSF-1 bind to the same receptor and display overlapping functions [24,25], both ligands show no structural similarities [26]. CSF-1R is expressed on cells of mononuclear phagocyte lineage (e.g. monocytes, M, DC) and myeloid precursors. Besides, CSF-1R is also detected in other cells (FLS [15] and osteoclasts [27][28][29]), which are also implicated in RA, indicating that the role of IL-34/ CSF-1R axis may not be restricted only to the immune system.
However, our knowledge of IL-34 functions mediated by these receptors is limited. So far we only know that: (1) PTP- activation by IL-34 induces phosphorylation of focal adhesion kinase (FAK) and paxillin in glioblastoma cells, which in turn restrains signaling pathways associated with proliferation, clonogenicity and motility [30]; (2) IL-34-mediated syndecan-1 activation modulates CSF-1R signaling pathways, but enhancing the migratory capacity of myeloid cells [31]. Collectively, increasing evidence indicates that IL-34-mediated activation of PTP- and syndecan-1 has a negative effect on CSF-1R signaling. It is possible that IL-34 directly acts on T and B lymphocytes via PTP- (and syndecan-1), as PTP- protein was detected in T and B lymphocytes in renal biopsies from mice with advanced lupus nephritis [32]. Interestingly, M were also positive for PTP- in this study [32], although transcriptional PTP- expression is not evident in in vitro generated bone marrowderived M before and after stimulation (Supplemental Figure 1 in [16]). The immunological functions of IL-34-induced PTP- and syndecan-1 are so far unclear and deserve future investigations.
Nevertheless, the effects of IL-34/CSF-1R axis on M are unambiguous as CSF-1R signaling has been well-studied for its impact on M biology [33] and is known to be important for M expansion in arthritic tissue. In RA, M number positively correlates with the disease severity [34][35][36]. Along these lines, local IL-34 injection during collagen-induced murine arthritis was associated with RA pathology [37]. IL-34-dependent mechanisms, which may support RA pathogenesis, are suggested as follows: (1)

The Impact of IL-34 on T Lymphocytes
The initial events in the pathogenesis of RA comprise two steps: [11]. This was the first study, which suggested a link between IL-34 and Th17 cells (Table 1). Similarly, the link between IL-34 and IL-17 expression is also found in other inflammatory diseases, such as Sjögren's syndrome, where IL-34 is suggested to regulate monocytes and/or M, which are involved in the pathogenesis [18]. Over the last three years, several studies have focused on identifying the molecular mechanisms that underlie the link between IL-34 and IL-17 and found that IL-34 stimulates FLS [15,42] and/or monocytes [42,43] to express IL-17 (Table 1). Upregulation of IL-17 expression in the synovium of mice with collagen-induced arthritis [37] Th17 Human monocyte cell line THP-1 Upregulation of IL-6 (plus IL-23, IL-21, IL-1b) expression in THP-1 leading to the increased numbers of Th17 cells in a THP-1-CD4 + T co-culture system

Funding Statement
These studies are funded by Biogen, Inc.

Disclosures
JHB is an employee of Biogen, Inc.