Syndecan-1 regulates the biological activities of interleukin-34

Abstract

IL-34 is a challenging cytokine sharing functional similarities with M-CSF through M-CSFR activation. It also plays a singular role that has recently been explained in the brain, through a binding to the receptor protein tyrosine phosphatase RPTPβ/ζ. The aim of this paper was to look for alternative binding of IL-34 on other cell types. Myeloid cells (HL-60, U-937, THP-1) were used as cells intrinsically expressing M-CSFR, and M-CSFR was expressed in TF-1 and HEK293 cells. IL-34 binding was studied by Scatchard and binding inhibition assays, using 125I-radiolabelled cytokines, and surface plasmon resonance. M-CSFR activation was analysed by Western blot after glycosaminoglycans abrasion, syndecan-1 overexpression or repression and addition of a blocking anti-syndecan antibody. M-CSF and IL-34 induced different patterns of M-CSFR phosphorylations, suggesting the existence of alternative binding for IL-34. Binding experiments and chondroitinase treatment confirmed low affinity binding to chondroitin sulphate chains on cells lacking both M-CSFR and RPTPβ/ζ. Amongst the proteoglycans with chondroitin sulphate chains, syndecan-1 was able to modulate the IL-34-induced M-CSFR signalling pathways. Interestingly, IL-34 induced the migration of syndecan-1 expressing cells. Indeed, IL-34 significantly increased the migration of THP-1 and M2a macrophages that was inhibited by addition of a blocking anti-syndecan-1 antibody. This paper provides evidence of alternative binding of IL-34 to chondroitin sulphates and syndecan-1 at the cell surface that modulates M-CSFR activation. In addition, IL-34-induced myeloid cell migration is a syndecan-1 dependent mechanism.

IL-34 and M-CSF form a novel heteromeric cytokine and regulate the M-CSF receptor activation and localization

“…In addition to the already identified functions of IL-34 and M-CSF in exacerbated macrophage activation (bowel diseases, liver fibrosis, chronic skin inflammation, arthritis, etc. ), this new heteromeric cytokine M-CSF/IL-34 which may differentially regulates the activation/localization of M-CSFR strengthens the global therapeutic approaches for blocking all biological functions coming from these molecules [7,8,[45][46][47][48][49][50][51].…”

“…Our molecular docking studies predicted a 2:2 interaction without any disulfide bond, which is able to bind to the M-CSFR, unlike a single M-CSF/IL-34 heterodimer. The exact functional implication of this new oligomeric cytokine still needs to be explored and must now be analysed in the light of the receptor protein tyrosine phosphatase b/f (RPTP b/f) identified as a new receptor for IL-34 [44], not expressed in the CD14 + and myeloid cells analysed in the present study [51]. The involvement of these oligomeric cytokine should be also investigated in light of syndecan-1which has been recently identified as new IL-34 effector [51].…”

“…The exact functional implication of this new oligomeric cytokine still needs to be explored and must now be analysed in the light of the receptor protein tyrosine phosphatase b/f (RPTP b/f) identified as a new receptor for IL-34 [44], not expressed in the CD14 + and myeloid cells analysed in the present study [51]. The involvement of these oligomeric cytokine should be also investigated in light of syndecan-1which has been recently identified as new IL-34 effector [51]. As with the IL17A/IL17F and IL-17RA/IL-17RC systems, the heteromeric M-CSF/IL-34 may regulate IL-34 and M-CSF functions through one receptor or another and the heteromer may also interact with both M-CSFR and RPTP b/f receptors.…”

Cytokines in the pathogenesis of rheumatoid arthritis: new players and therapeutic targets

“…Upon binding to CSF-1R, IL-34 stimulates monocytes and macrophages through extracellular signal-regulated kinase (ERK) 1/2 or AKT phosphorylation. Recent data, however, demonstrated that IL-34 could also bind chondroitin sulphate chains, such as PTP-ζ and syndecan-1, but with lower affinity [133,134]. This is of particular importance in tumor biology as these receptors are up-regulated in several cancer types.…”

Receptor-Type Protein-Tyrosine Phosphatase ζ and Colony Stimulating Factor-1 Receptor in the Intestine: Cellular Expression and Cytokine- and Chemokine Responses by Interleukin-34 and Colony Stimulating Factor-1

“…In this study, we used the Caco-2 cell line, to confirm this data, further studies investigating primary colon epithelial cells should be performed. Data on the expression of PTPRZ1 in monocytic THP-1 cells are conflicting where Booker and colleagues showed increased expression after ligand binding Seganily and colleagues reported no expression of PTPRZ1 in THP-1 cells [35, 36]. We used PBMCs and thus neutrophils were excluded by ficoll isolation.…”