Ageing-Related Macrophage Polarisation in the Trigeminal Ganglion Enhances Incisional Intraoral Pain.

Abstract

Although macrophage polarisation in the trigeminal ganglion (TG) is crucial in orofacial pain hypersensitivity, the effect of ageing-related changes and their involvement in intra-oral nociception remains unclear. We assessed the effect of ageing-related macrophage polarisation in TG on intra-oral mechanical pain hypersensitivity following palatal mucosal incision using senescence-accelerated mice (SAM)-prone8 (SAMP8) and SAM-resistant 1 (SAMR1). Mechanical head-withdrawal reflex threshold (MHWRT) of the palatal mucosa was measured for 21 days after palatal mucosal incision. On days 3 and 14, the abundance of Iba-1-immunoreactive (IR) cells, CD11c-IR cells (pro-inflammatory macrophages (M1)), C-C motif chemokine ligand 2 (CCL2)-IR M1-macrophages, CD206-IR cells (anti-inflammatory macrophages (M2)) and transforming growth factor-β (TGF-β)-IR M2-macrophages in the TG was analysed. The effect of continuous intra-TG administration of CCL2-neutralising antibody or recombinant-CCL2 on MHWRT was examined. Incision-induced decrease in MHWRT was enhanced in SAMP8 compared with that in SAMR1. On days 3 and 14, the number of CCL2-IR M1-macrophages in TG was increased in SAMP8 compared with that in SAMR1. CCL2-neutralising antibody suppressed, whereas recombinant-CCL2 increased pain hypersensitivity in SAMP8. Mechanical pain hypersensitivity after oral mucosal injury is potentiated and sustained by age-related enhancement of CCL2 signalling via M1-macrophage hyperactivation in TG.