Cerebrospinal Fluid Metabolites Mediate Immune Cell Effects on Chronic Pain.

BACKGROUND: While immune cells have been implicated in chronic pain (CP), the causal relationships between immune cells and CP across different body regions, as well as the potential mediating role of cerebrospinal fluid (CSF) metabolites on CP, remain unclear. METHODS: In this study, we inspected the causal relationship between circulating immune cell subsets and CP in the neck/shoulder, back, hip, and knee by using a two-sample Mendelian randomization (MR) analysis. In addition, a two-step MR approach was applied to assess the mediating role of CSF metabolites linking immune cells and CP, identifying potential mediators and quantifying their mediation effects. The robustness of the MR findings was assessed according to comprehensive sensitivity analyses. RESULTS: MR analysis revealed 76 immune cells were strongly associated with CP across four regions (neck/shoulder, back, hip, and knee), along with 40 CSF metabolites significantly linked to CP. All associations demonstrated no evidence of reverse causation. In the two-step MR mediation analysis, the following potential mediators were identified: (1) For chronic neck/shoulder pain (CNP): 3-Hydroxy-3-methylglutarate (12.9% mediation proportion) for IgD⁻ CD27⁻ absolute cell count (AC), and X-18887 for both CD16 on CD14⁺ CD16⁺ monocytes (5.0%) and IgD on IgD⁺ CD38⁻ cells (4.3%); (2) For chronic back pain (CBP): X-14056 for CD20 on IgD⁺ CD38bright cells (22.7%) and CD20 on transitional B cells (17.6%), and Beta-hydroxyisovalerate (8.6%) for CD3⁻ lymphocyte AC; (3) For chronic knee pain (CKP): Phenol sulfate for CD45RA on naive CD8br cells (20.0%) and CD20 on unsw mem cells (16.7%); Arginine for CD27 on memory B cells (13.6%); and N-Acetyl-aspartyl-glutamate (13.0%) for IgD on IgD⁺ CD38⁻ cells. The robustness of these findings was further confirmed through sensitivity analyses. CONCLUSIONS: These findings underscore the mediating role of CSF metabolites in the immune cell-chronic pain axis, providing mechanistic insights into CP pathogenesis and potential therapeutic targets across distinct pain regions.