Infiltrated macrophages aggravate TMJOA chronic pain via Piezo2 in IB4 + - TG neurons

Abstract Temporomandibular joint osteoarthritis (TMJOA) chronic pain is one of the orofacial pains that result in limitations in chewing function and a decline in quality of life. Currently, therapies for TMJOA chronic pain are inadequate due to a lack of understanding of its underlying mechanism. Recent research has shown that macrophages in the ganglia play a role in the development of chronic pain. Piezo2, an ion channel for nociception, has potentially been discovered in ganglia neurons. In this study, we found that infiltrated macrophages, rather than tissue-resident macrophages in trigeminal ganglia (TGs), are involved in monosodium iodoacetate (MIA)-induced TMJOA chronic pain in rats. The number of infiltrated macrophages is positively correlated with the elevation of Piezo2 in the trigeminal ganglion (TG) neurons of TMJOA rats. Consistently, depletion of infiltrated macrophages through Cl 2 MDP tail intravenous injections leads to a down-regulation of Piezo2 in TG neurons. Additionally, overexpression of Piezo2 in TG neurons through adeno-associated virus 9 (AAV9)-Piezo2 targeting rats' neurons intracerebral injection reverses the alleviation effect of infiltrated macrophages depletion on TMJOA chronic pain in rats. Furthermore, infiltrated macrophages primarily mediate the expression of Piezo2 in IB4 + -TG neurons of TMJOA chronic pain rats. Moreover, an ex vivo study demonstrates that IL-1β and TNF-α, the main pro-inflammatory cytokines secreted by infiltrated macrophages, induce the activation of rat Dil + -TG neurons by up-regulating Piezo2. This study demonstrates that infiltrated macrophages contribute to MIA-induced TMJOA chronic pain by upregulating the expression of Piezo2 in IB4 + -TG neurons, providing new insights into the mechanism of TMJOA chronic pain.