The Vagus Nerve-Macrophage Connection: Tuning the Rheostat of Regenerative Medicine

Chronic musculoskeletal disorders, including osteoarthritis, rheumatoid arthritis, and tendinopathies, converge on persistent synovial inflammation, matrix catabolism, and impaired repair. This review synthesizes molecular evidence that the cholinergic anti-inflammatory pathway (CAP), the efferent vagal arm of the inflammatory reflex, behaves as a rheostat of the musculoskeletal microenvironment. Activation of the α7 nicotinic acetylcholine receptor (α7nAChR) on macrophages, chondrocytes, osteoblasts, and synoviocytes suppresses nuclear factor-κB (NF-κB) and NLRP3 inflammasome signaling, downregulates MMP-1, MMP-3, and MMP-13, and reduces osteoblast RANKL production; effects on OPG and on the RANKL/OPG ratio under vagal stimulation remain uncharacterized, while favoring a pro-resolution M2-like macrophage program; context-dependent pro-inflammatory responses have also been reported. Bidirectional CAP and mesenchymal stromal cell (MSC) crosstalk indicates that MSCs both sense cholinergic cues and require an intact vagal arc for full immunomodulation. Along the gut-vagus-joint axis, dysbiosis and endotoxin translocation attenuate vagal signaling and amplify systemic inflammatory tone. Because orthobiologics such as platelet-rich plasma, bone marrow aspirate concentrate, and MSCs act within this milieu, cholinergic tone appears associated with the terrain that conditions their efficacy. Heart rate variability stratification and vagal neuromodulation may represent testable adjuncts, although prospective validation in orthobiologic populations remains absent. Preclinical and early clinical evidence is critically appraised throughout.