Dorsal root ganglia CX3CR1 expressing monocytes/macrophages contribute to arthritis pain

Pain is a persistent symptom of Rheumatoid Arthritis, and the K/BxN serum transfer model recapitulates both association and dissociation between pain and joint inflammation in RA. Furthermore, this model features monocyte/macrophage infiltration in joints and lumbar dorsal root ganglia (DRG), where these immune cells are close to nociceptive neurons. We focussed on CX(3)CR(1)-monocyte/macrophage trafficking and show that at peak paw swelling associated with nociception, CX(3)CR(1) deletion altered neither swelling nor macrophage infiltration/phenotype in paws. However, acute nociception and DRG non-classical monocyte numbers were reduced in CX(3)CR(1)(GFP/GFP) (KO) compared to CX(3)CR(1)(+/GFP) (WT). Nociception that persisted despite swelling had resolved was attenuated in KO and correlated with DRG macrophages displaying M2-like phenotype. Still in the DRG, neurons up-regulated neuropeptide CGRP and olcegepant treatment reduced acute swelling, nociception, and leukocyte infiltration in paws and DRG. We delineate in-vitro a signalling pathway showing that CGRP liberates the CX(3)CR(1) ligand fractalkine (FKN) from endothelium, and in bone marrow-derived macrophages, FKN promotes activation of intracellular kinases, polarisation towards M1-like phenotype and release of pro-nociceptive IL-6. These data implicate non-classical CX(3)CR(1)-expressing monocyte and macrophage recruitment into the DRG in initiation and maintenance of arthritis pain.