Symmetrical joint inflammation is formed by a sensory neural connection between bilateral joints in a rheumatoid arthritis model
Takuto Ohki1, Daisuke Kamimura1, Yasunobu Arima1,and Masaaki Murakami1 1Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, 060-0815, Japan
Symmetrical pathology in various inflammatory diseases including rheumatoid arthritis (RA), psoriasis, pulmonary fibrosis, glomerulonephritis, and sympathetic ophthalmitis could be formed by a direct neurological connection between the affected regions, because the nervous system integrates functions and movements between both sides of the body. However, the critical neural pathway and key molecules including neurotransmitters responsible for the symmetrical symptoms are still unknown. We revealed that symetrical inflammation in the ankle joints is formed by sensory neural connections via interneurons in the lower thoracic cords by using F759 mouse, a mouse model of RA. F759 mice have Y759F amino acid substitution in gp130, the IL-6 signal transducer in the IL-6 receptor complex, which leads to continuous IL-6-mediated STAT3 activation, because F759 mice have a substituted Y759, which is the binding site of SOCS3 for the negative regulation of IL-6 signaling after phosphorylation. We have previously shown that direct ankle-joint injections of IL-17A and IL-6 in F759 mice induce an RA-like disease. Important advantage of this cytokine-induced arthritis model is that we can induce the RA-like disease both uni- and bilaterally, which enables us to analyze the neural signal direction from one side of ankle joint inflammation to the other. We then found that symmetrical ankle joint inflammation is suppressed by surgical ablation or pharmacological inhibition of this sensory neural interaction between bilateral joints. We identified ATP, which works as both a neurotransmitter and pro-inflammatory factor, as a key molecule to link the local inflammation and neural pathway to induce the symmetrical joint inflammation. We verified this mechanism operates the symmetrical joint inflammation in another RA model, collagen-induced arthritis. Thus, blockades of this regional sensory neural interaction by suppressing ATP or suppressing the excessive activation of sensory neurons could be a new therapy for inflammatory diseases with symmetric symptoms.
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