Complement component 3 promotes regeneration of olfactory receptor neurons.

Abstract

Olfactory receptor neurons (ORNs) in the olfactory epithelium are characterized by high regenerative capacity even after birth, but the molecular mechanisms involved in ORN regeneration remain unclear. Complement component 3 (C3) has been shown to promote tissue regeneration, so we hypothesized that C3 activates innate immunity and also promotes regeneration of ORNs. Here, we investigate the role of C3 in ORN regeneration. We used C3 knockout (KO) and wild-type C57BL/6J mice in this study to examine the olfactory regeneration process for 42 days after methimazole-induced olfactory disorder. To compare the regenerative process after ORN damage between C3 KO and wild-type mice, we conducted olfactory behavioral tests and immunohistological analysis and examined growth factors and inflammatory cell induction. C3 KO mice showed delayed olfactory recovery with lower olfactory epithelial thickness. In C3 KO mice, ORN maturation was delayed in association with increased accumulation of immature ORNs. In the normal ORN regeneration process, undesirable immature ORNs are produced and eliminated by apoptosis. C3 deficiency reduced neutrophils induced during ORN regeneration, suggesting the involvement of C3 in ORN regeneration through neutrophil-dependent elimination of undesired ORNs. C3 is therefore suggested to have promoted ORN regeneration by preventing the accumulation of immature ORNs. In addition, C3 may assist ORN maturation by participating in ORN axon selection like synaptic pruning. Our results indicate that C3, which is activated during pathogen infection, also promotes recovery from ORN damage. These findings may lead to new therapeutic strategies for olfactory disorder.