SKULL BONE MARROW AND PERIPHERAL IMMUNE REACTIVITY IN CHRONIC PAIN: A TSPO PET/MRI AND CYTOKINE STUDY

Chronic pain is increasingly recognized as a neuroinflammatory condition involving interactions between peripheral immune processes and the central nervous system. The skull bone marrow (SBM) is a critical interface in this peripheral-central immune axis, yet cytokine signatures and SBM activation patterns in distinct chronic pain conditions remain unclear.
We assessed lipopolysaccharide (LPS)-induced cytokine reactivity in peripheral blood cells from patients with chronic lower back pain (cLBP; n = 13) and knee osteoarthritis (KOA; n = 17), alongside healthy controls (n = 10). Cytokine fold changes were analyzed in relation to pain intensity, pain interference, depression, and anxiety using partial linear regression adjusting for baseline cytokine levels. SBM immune cell density was quantified via [¹¹C]PBR28 PET/MRI, indexing 18 kDa translocator protein (TSPO) expression.
Compared to controls, only cLBP patients exhibited significantly reduced LPS-induced IL-4 and IL-10 reactivity (p<0.05). In cLBP, pain intensity showed associations with IL-1β, TNF-α, GM-CSF, and IFN-γ reactivity (p< 0.05), with a trend for IL-6. In contrast, KOA demonstrated broader clinical associations, with both pain intensity and pain interference correlating with IL-1β, IL-6, MCP-1, and MIP-1α (p< 0.05). Notably, depressive and anxiety symptoms correlated with IL-1 receptor antagonist (IL-1RA) reactivity exclusively in cLBP (p< 0.001). Voxelwise analyses revealed significant associations between SBM TSPO signal and IL-1RA, IL-6, IL-8, and GM-CSF reactivity (p< 0.01).
These findings reveal condition-specific peripheral immune signatures in chronic pain and provide in vivo evidence linking SBM activation with peripheral cytokine reactivity, supporting a functional skull-immune-brain axis in human pain pathophysiology.