Abstract
Following peripheral nerve injury, dysregulations of certain non-coding microRNAs (miRNAs) occur in Schwann cells. Whether these alterations are the result of local inflammation and/or correlate with perturbations in the expression profile of the protective vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating polypeptide (PACAP) system is currently unknown. To address these issues, we aimed at profiling the expression of selected miRNAs in the rat RT4 Schwann cell line. Cells exposed to lipopolysaccharide (LPS), to mimic the local inflammatory milieu, were appraised by real-time qPCR, Western blot and ELISAs. We found that upon LPS treatment, levels of pro-inflammatory cytokines (IL-1β, -6, -18, -17A, MCP-1 and TNFα) increased in a time-dependent manner. Unexpectedly, the expression levels of VIP and PACAP were also increased. Conversely, levels of VPAC1 and VPAC2 receptors were reduced. Downregulated miRNAs included miR-181b, -145, -27a, -340 and -132 whereas upregulated ones were miR-21, -206, -146a, -34a, -155, -204 and -29a, respectively. Regression analyses revealed that a subset of the identified miRNAs inversely correlated with the expression of VPAC1 and VPAC2 receptors. In conclusion, these findings identified a novel subset of miRNAs that are dysregulated by immune challenge whose activities might elicit a regulatory function on the VIP/PACAP system.
Highlights
Axons of the peripheral nervous system (PNS), as opposed to those of the central nervous system (CNS), exhibit high capacity of regeneration after lesion
We have unveiled a subset of miRNAs whose expression levels are dysregulated in RT4 Schwann cells (SCs) in vitro when exposed to an immune challenge with LPS
We performed these investigations in the attempt to gain mechanistic insights that could aid in modelling the cell behavior of SCs in vivo when exposed to the local inflammatory microenvironment found following nerve injury
Summary
Axons of the peripheral nervous system (PNS), as opposed to those of the central nervous system (CNS), exhibit high capacity of regeneration after lesion. Dedifferentiated SCs shut down the myelination program and acquire new phenotypes coordinately to support nerve repair. These phenotypes include (1) secretion of neurotrophic factors to promote axonal survival; (2) clearance of myelin debris to generate a favorable environment for axonal regrowth; (3) initiation of inflammatory responses to promote wound healing; and (4) proliferation to replace dead cells [1,3]
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