Modulating synovial macrophage responses to nociceptive signals attenuates inflammation in rheumatoid arthritis.

Pain and inflammation are the most common symptoms experienced by patients with acute rheumatoid arthritis (RA). Immunomodulatory signals released by nociceptive nerves play an important role in various infectious and inflammatory diseases. In this study, we found that ablation of nociceptive nerves exacerbated joint inflammation in an antigen-induced arthritis model. Our findings revealed that immune complex could independently and directly activate nociceptive nerves in the synovium, initiating pain signals that subsequently modulate inflammation through the neuropeptide calcitonin gene-related peptide (CGRP). Specifically, CGRP bound to the receptor activity-modifying protein 1 and calcitonin receptor-like receptor (Calcrl) complex on CX3CR1(+) synovial macrophages, suppressing the expression of inflammatory factors and chemokines while inhibiting the recruitment of immune cells. However, prolonged activation of nociceptive nerves led to the downregulation of Calcrl in synovial macrophages, reducing their sensitivity to CGRP. This diminished sensitivity implied that the excessive release of pain-related transmitters failed to suppress inflammation effectively. To address this, we overexpressed Calcrl in CX3CR1(+) synovial macrophages by transfecting them with recombinant adeno-associated virus, demonstrating that this approach alleviates joint inflammation without intensifying pain. These findings highlight the therapeutic potential of targeting neuroimmune interactions to manage RA.