Infiltrated Macrophages Aggravate TMJOA Chronic Pain via Piezo2 in IB4 + ‐ TG Neurons

ABSTRACT Objective Recent research indicates that macrophages in ganglia are linked to chronic pain, with Piezo2 ion channels playing a key role in pain sensation. Our study aims to elucidate the interplay between macrophages and Piezo2 in temporomandibular joint osteoarthritis (TMJOA) chronic pain. Materials and Methods We induced TMJOA chronic pain in rats via articular injection of monosodium iodoacetate (MIA). We then depleted macrophages using clodronate liposomes and overexpressed Piezo2 in trigeminal ganglion (TG) neurons with adeno‐associated virus 9 (AAV9)‐Piezo2 in TMJOA rats. To explore the connection between macrophages and Piezo2, we employed immunofluorescence, in vitro studies, and the Rat Grimace Scale (RGS) to evaluate pain thresholds in TMJOA rats. Results A positive correlation was observed between macrophage infiltration and Piezo2 upregulation in TG neurons of TMJOA rats. Depletion of infiltrated macrophages downregulated Piezo2 in TG neurons, while Piezo2 overexpression negated the pain‐relieving effects of infiltrated macrophage depletion in TMJOA rats. Macrophages primarily influenced Piezo2 expression in IB4 + – TG neurons of TMJOA chronic pain rats. Ex vivo studies revealed that infiltrated macrophage‐derived IL‐1β and TNF‐α cytokines activate Dil + −TG neurons by upregulating Piezo2 in TMJOA rats. Conclusions Infiltrated macrophages exacerbate MIA‐induced TMJOA chronic pain by upregulating Piezo2 expression in IB4 + ‐TG neurons.