C5L2 Silencing in Human Pulp Fibroblasts Enhances Nerve Outgrowth Under Lipoteichoic Acid Stimulation

We recently reported that caries-associated C5a receptor (C5aR) expression and activation result in up-regulation of brain-derived neurotropic factor secretion by pulp fibroblasts inducing prominent neurite outgrowth toward the carious site. Our data further showed a negative regulation of this brain-derived neurotropic factor secretion by C5L2, another C5aR. C5L2 was considered a nonfunctional receptor and thus has received much less attention than C5aR. The aim of this study was to identify the role of C5L2 in pulp fibroblast-mediated neurite outgrowth.

In this study, lipoteichoic acid (LTA) was used to mimic dental caries-like inflammation. To evaluate the role of C5L2 in pulp neurite outgrowth, human pulp fibroblasts were C5L2 small interfering RNA silenced and cocultured with human neurons in a nerve growth assay system.

C5L2 silencing drastically increased the neurite outgrowth toward the LTA-stimulated pulp fibroblasts. The number of neurites detected was increased in the LTA-treated pulp fibroblasts.

Our results show that C5L2 constitutes a negative regulator of the neurite outgrowth under LTA stimulation. Of the events occurring during dentin-pulp regeneration, nerve regeneration is the key factor for maintaining tooth viability after infection or injury. Our study provides a foundation for creating therapeutic tools that target pulp fibroblasts during pulp/nerve regeneration.