Neuroimmune interactions in arthritis: linking pain sensitisation and inflammation

Abstract Arthritis represents a group of chronic joint diseases characterised by persistent inflammation, pain, and progressive tissue damage. Despite advances in therapeutic management, many patients experience incomplete symptom relief, highlighting the need to better understand the underlying mechanisms that sustain inflammation and pain. Emerging evidence indicates that neuroimmune interactions within the joint microenvironment play a central role in the pathogenesis of arthritis. The synovium, a thin membrane that lines the joint cavity, is the primary site of pathology in arthritis and serves as a dynamic interface integrating immune, vascular, and neural components. Under physiological conditions, tissue-resident macrophages, fibroblasts, and sensory nerve fibres maintain joint homeostasis. However, during arthritis, the synovium undergoes extensive remodelling, including hyperplasia, angiogenesis, and nerve fibre sprouting, which together amplify inflammatory and nociceptive signalling. Distinct macrophage subsets within the synovium exhibit specialised roles in mediating inflammation and communicating with neurons. Macrophage-derived cytokines such as IL-1β, IL-6, and TNF-α can directly sensitise nociceptors, whilst chemokines like CCL2 engage neuronal receptors to enhance excitability. Conversely, activated sensory neurons release neuropeptides such as calcitonin gene-related peptide (CGRP) and substance P (SP), which can modulate immune cell behaviour. Sympathetic signalling further contributes to immune modulation and correlates with disease severity. Together, these studies reveal that arthritis progression and chronic pain are shaped by reciprocal signalling between the nervous and immune systems. Understanding these complex pathways offers new perspectives for therapeutic intervention, suggesting that targeting neuroimmune crosstalk could provide dual benefits—reducing inflammation whilst alleviating chronic pain in arthritic disease.