Dorsal root ganglion macrophages mediate osteoarthritis pain via disruption of sensory neuron perineuronal nets.

Osteoarthritis (OA) is a widespread joint disease marked by progressive degeneration and chronic joint pain, but effective analgesic therapies are lacking. This study investigated the role of dorsal root ganglion (DRG) macrophages in mediating OA pain, focusing on their effect on perineuronal nets (PNNs) surrounding sensory neurons. In a mono-iodoacetate (MIA)-induced OA model, disruption of PNNs in the DRG, reflected by reduced WFA-labeled PNNs, coincided with mechanical allodynia, thermal hyperalgesia, and reduced weight bearing. Disruption of PNNs via chondroitinase ABC (chABC) or genetic knockdown of Acan worsened pain and increased spontaneous and mechanically-evoked activity of C-fibers. Conversely, macrophage-specific ablation preserved PNNs and alleviated pain. Mechanistically, DRG macrophages were activated via IL 33/ST2 signaling and were associated with reduced PNN integrity. Targeting ST2 in macrophages preserved PNN integrity, reduced macrophage activation, and significantly relieved OA pain. Our results support macrophage-mediated PNN disruption as a key mechanism in OA pain and propose the IL-33/ST2 axis may represent a potential therapeutic target.