Interleukin-17 impedes Schwann cell-mediated myelination

Abstract

BackgroundPro-inflammatory cytokines are known to have deleterious effects on Schwann cells (SCs). Interleukin 17 (IL-17) is a potent pro-inflammatory cytokine that exhibits relevant effects during inflammation in the peripheral nervous system (PNS), and IL-17-secreting cells have been reported within the endoneurium in proximity to the SCs.MethodsHere, we analyzed the effects of IL-17 on myelination and the immunological properties of SCs. Dorsal root ganglia (DRG) co-cultures containing neurons and SCs from BL6 mice were used to define the impact of IL-17 on myelination and on SC differentiation; primary SCs were analyzed for RNA and protein expression to define the putative immunological alignment of the SCs.ResultsSCs were found to functionally express the IL-17 receptors A and B. In DRG cultures, stimulation with IL-17 resulted in reduced myelin synthesis, while pro-myelin gene expression was suppressed at the mRNA level. Neuronal outgrowth and SC viability, as well as structural myelin formation, remained unaffected. Co-cultures exhibited SC-relevant pro-inflammatory markers, such as matrix metalloproteinase 9 and SCs significantly increased the expression of the major histocompatibility complex (MHC) I and exhibited a slight, nonsignificant increase in expression of MHCII, and a transporter associated with antigen presentation (TAP) II molecules relevant for antigen processing and presentation.ConclusionsIL-17 may act as a myelin-suppressive mediator in the peripheral nerve, directly propagating SC-mediated demyelination, paralleled by an inflammatory alignment of the SCs. Further analyses are warranted to elucidate the role of IL-17 during inflammation in the PNS in vivo, which could be useful in the development of target therapies.

Deciphering immune mechanisms in chronic inflammatory demyelinating polyneuropathies

“…Moreover, in an inflammation/ injury model, where peripheral neuropathy was induced in C57BL/6 mice by partial ligation of the sciatic nerve, mice lacking IL-17 had significantly fewer infiltrating T cells and macrophages and decreased pain hypersensitivity (36). Moreover, IL-17 may have direct effects on Schwann cells, through inhibition of myelination and upregulation of MHC-I (37). Further studies are needed to determine whether both IFN-γ and IL-17 play critical roles in the immunopathology of CIDP.…”

Coding transcriptome analyses reveal altered functions underlying immunotolerance of PEG-fused rat sciatic nerve allografts

“…IFN-γ serves many functions in rejection, such as maintaining T cell survival, inducing MHC expression in nearby cells and inducing macrophages to produce pro-inflammatory cytokines and ROS (33). IL-17 is produced by Th17 cells and stimulates proinflammatory cytokine production, antigen presentation, and may suppress myelin production in Schwann cells (34). We observed that PEG-fused PNAs exhibit significant downregulation of each of these critical cytokines, as well as effector molecules FASL, PRF1, and GZMB that are commonly employed by cytotoxic T cells to kill donor cells.…”

The alternatively spliced fibronectin CS1 isoform regulates IL-17A levels and mechanical allodynia after peripheral nerve injury

“…Subsequently, FN-CS1 mediates T cell adhesion, migration, and rolling along myelinated fibers [ 25 – 28 , 52 – 54 ], which through secretion of algesic IL-17A [ 13 ] helps sustain the adaptive immune response and the persistent state of mechanical allodynia. At the later stage post-nerve damage, IL-17A release from Th17 cells may help sustain mechanical hypersensitivity by impeding Schwann-cell-mediated remyelination of sensory neurons [ 55 ].…”