The anaphylatoxin C5a constitutes a powerful fragment generated by complement system activation. Interestingly, this complement active fragment is also an important mediator of tissue regeneration. Recent findings suggest that C5a could be an initial signal orchestrating pulp nerve sprouting beneath carious injury, a critical step in dentin-pulp regeneration. Indeed, the expression and activation of the C5a active receptor (C5aR/CD88) by injured pulp fibroblasts controls the direction of neurite outgrowth toward carious injuries by modulating the secretion of brain-derived neurotrophic factor (BDNF) by pulp fibroblasts. A second C5a receptor, C5L2, has also been cloned but has received much less attention because its interaction with the ligand induces no signaling. This work aims to investigate the role of C5L2 in pulp nerve regeneration in the secretion of BDNF by pulp fibroblasts under sites of carious injury. Using fluorescence immunostaining on human tooth sections in vivo and on primary human pulp fibroblasts in vitro, the authors reveal that C5L2 and C5aR are co-expressed by pulp fibroblasts under lipoteichoic acid (LTA) stimulation. Moreover, silencing C5L2 significantly increases BDNF secretion by LTA-stimulated pulp fibroblasts. Finally, an analysis of the subcellular distribution of C5aR and C5L2 indicates that the negative regulation of BDNF secretion by C5L2 correlates with C5aR activation and its subsequent intracellular co-localization with C5L2. Overall, the current study sheds light on the mechanism of pulp nerve regeneration by identifying C5L2 as a negative regulator of BDNF secretion by pulp fibroblasts under carious teeth. This knowledge significantly increases the understanding of the functional mechanism linking C5aR and C5L2 in pulp nerve regeneration, which may be useful in future dentin-pulp engineering strategies that target fibroblast C5L2 to induce pulp innervation.