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

• DOI: 10.1016/j.bbi.2022.09.008
• Publication Date: 2022-09-14T16:24:02Z
• Authors: Silvia Oggero; Chiara Cecconello; Rita Silva; Lynda Zeboudj; George Sideris-La...; Mauro Perretti; Marzia Malcangio
• Keywords: 0301 basic medicine; Chemokine CX3CL1; Interleukin-6; Arthritis; Calcitonin Gene-Related Peptide; Macrophages; CX3C Chemokine Receptor 1; 610; Pain; 600; Ligands; Fractalkine; Article; Monocytes; Arthritis, Rheumatoid; 03 medical and health sciences; Ganglia, Spinal; Humans; CGRP

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 CX3CR1-monocyte/macrophage trafficking and show that at peak paw swelling associated with nociception, CX3CR1 deletion altered neither swelling nor macrophage infiltration/phenotype in paws. However, acute nociception and DRG non-classical monocyte numbers were reduced in CX3CR1GFP/GFP (KO) compared to CX3CR1+/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 CX3CR1 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 CX3CR1-expressing monocyte and macrophage recruitment into the DRG in initiation and maintenance of arthritis pain.