Abstract
BackgroundSchwann cells are the myelinating glial cells of the peripheral nervous system and exert important regenerative functions revealing them as central repair components of many peripheral nerve pathologies. Intravenous immunoglobulins (IVIG) are widely used to treat autoimmune and inflammatory diseases including immune-mediated neuropathies. Nevertheless, promotion of peripheral nerve regeneration is currently an unmet therapeutical goal. We therefore examined whether immunoglobulins affect glial cell homeostasis, differentiation, and Schwann cell dependent nerve regenerative processes.MethodsThe responses of different primary Schwann cell culture models to IVIG were investigated: immature or differentiation competent Schwann cells, myelinating neuron/glial cocultures, and dorsal root ganglion explants. Immature or differentiating Schwann cells were used to study cellular proliferation, morphology, and gene/protein expression. Myelination rates were determined using myelinating neuron/glia cocultures, whereas axonal outgrowth was assessed using non-myelinating dorsal root ganglion explants.ResultsWe found that IVIG specifically bind to Schwann cells and detected CD64 Fc receptor expression on their surface. In response to IVIG binding, Schwann cells reduced proliferation rates and accelerated growth of cellular protrusions. Furthermore, we observed that IVIG treatment transiently boosts myelin gene expression and myelination-related signaling pathways of immature cells, whereas in differentiating Schwann cells, myelin expression is enhanced on a long-term scale. Importantly, myelin gene upregulation was not detected upon application of IgG1 control antibodies. In addition, we demonstrate for the first time that Schwann cells secrete interleukin-18 upon IVIG stimulation and that this cytokine instructs these cells to promote axonal growth.ConclusionsWe conclude that IVIG can positively influence the Schwann cell differentiation process and that it enhances their regenerative potential.
Highlights
Schwann cells are the myelinating glial cells of the peripheral nervous system and exert important regenerative functions revealing them as central repair components of many peripheral nerve pathologies
Human immunoglobulins bind to the rat Schwann cell surface Several studies indicate that immunoglobulins may directly affect oligodendroglial cells, the myelinating glial cells of the central nervous system (CNS)
By applying antihuman F(ab′)2-specific and anti-human fragment crystallisable (Fc) gamma-specific antibodies (i.e., F(ab′)2 fragments), we could demonstrate that human immunoglobulins bind on the Schwann cell surface (Fig. 1a–f)
Summary
Schwann cells are the myelinating glial cells of the peripheral nervous system and exert important regenerative functions revealing them as central repair components of many peripheral nerve pathologies. Tzekova et al Journal of Neuroinflammation (2015) 12:107 presentation, secretion of cyto- and chemokines, expression of complement components, and surface receptors involved in pathogen recognition (reviewed in [4]) This immune competence along with the plastic differentiation potential of Schwann cells provide the PNS with a certain regeneration capacity and further indicates that these glial cells are central components of many, if not all, nerve pathologies. Nerve regeneration in the PNS faces limitations, in particular when it comes to inflammatory and inherited neuropathies, or in peripheral nerve pathologies induced by toxins, drugs, or in diabetic patients [5,6,7,8] For most of these neurological conditions, functional restoration of damaged axonal tracts and myelin sheaths represents the ultimate therapeutic goal which is, currently unmet. No current evidence exists indicating that IVIG directly affect Schwann cells, recent data point to a role of endogenous antibodies in rapid myelin clearance and axon regeneration after nerve injury [12]
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