ATP spreads inflammation to other limbs through crosstalk between sensory neurons and interneurons

Neural circuits between lesions are one mechanism through which local inflammation spreads to remote positions. Here, we show the inflammatory signal on one side of the joint is spread to the other side via sensory neuron-interneuron crosstalk, with ATP at the core. Surgical ablation or pharmacological inhibition of this neural pathway prevented inflammation development on the other side. Mechanistic analysis showed that ATP serves as both a neurotransmitter and an inflammation enhancer, thus acting as an intermediary between the local inflammation and neural pathway that induces inflammation on the other side. These results suggest blockade of this neural pathway, which is named the remote inflammation gateway reflex, may have therapeutic value for inflammatory diseases, particularly those, such as rheumatoid arthritis, in which inflammation spreads to remote positions. Local inflammation spreads to remote positions via sensory neuron-interneuron crosstalk using ATP. This neural pathway, or remote inflammation gateway reflex, may be a therapeutic target for inflammatory diseases with remote inflammation, such as rheumatoid arthritis.