The primary aim was to identify cytokines involved in blood borne, neuroimmune joint-to-CNS signalling in knee osteoarthritis (OA) patients. Monocyte chemoattractant protein 1 (MCP1) and Interleukin-8 (IL-8) were elevated in the cerebrospinal fluid (CSF) in patients indicating neuroinflammation. Significant positive correlations were found for MCP1 across CSF, serum and synovial fluid (SF), in female, but not male patients. The results revealed sex differences in neuroimmune signalling and implicated MCP1 in blood borne joint-to-CNS signalling in female patients. Symptom severity correlated with IL-6 and IL-8 levels in SF, but was inversely associated with IL-6 and IL-8 levels in CSF, indicating that neuroinflammation in OA may be an adaptive, possibly neuroprotective mechanism promoting symptom reduction.

Supplemental Digital Content is Available in the Text.A combination of clinical and preclinical data that support a role for the lysolipid LPC16:0 via acid-sensing ion channels 3 in chronic joint pain related to rheumatic diseases.

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The aim was to assess the activation and association of the NF-κB system across synovial membrane (SM) and articular cartilage (AC) in patients with knee osteoarthritis (OA) and ascertain its potential effects on catabolic mediator expression in advanced OA. SM and AC were obtained from 40 OA patients undergoing total knee arthroplasty and from 19 postmortem control subjects. NF-κB subunit RelA in nuclear and cytosolic fractions and NF-κB1-DNA binding in nuclear extracts was assessed by ELISA, whereas ,, ,, and gene expression were analyzed by reverse transcriptase-quantitative PCR in tissues. We observed higher SM nuclear RelA protein levels and upregulated NF-κB1-DNA binding in OA patients compared with postmortem controls. However, in AC, lower nuclear RelA levels were observed compared with cytosolic extracts in patients. Nuclear RelA levels correlated positively with NF-κB1-DNA binding in SM and AC in patients. SM and mRNA levels were upregulated, whereas and as well as AC were downregulated in patients compared with controls. In SM, nuclear RelA levels correlated positively with gene expression in patients. A negative correlation was observed between SM nuclear RelA levels and AC NF-κB1-DNA binding, and SM nuclear NF-κB1-DNA binding correlated negatively with AC and mRNA levels in patients. These findings highlight NF-κB-triggered cross-talk and feedback mechanisms between SM and AC in OA. Further, our findings strongly support a role for an activated NF-κB system in the transcriptional mechanism of inflammatory processes, especially in SM of patients with advanced OA.

Neuroinflammation and periphery-to-CNS neuroimmune cross-talk in patients with painful knee osteoarthritis (OA) are poorly understood. We utilized proximity extension assay to measure the level of 91 inflammatory proteins in CSF and serum from OA patients and controls. The patients had elevated levels of 48 proteins in CSF indicating neuroinflammation. Ten proteins were correlated between CSF and serum and potentially involved in periphery-to-CNS neuroimmune cross-talk. Seven CSF proteins, all with previously reported neuroprotective effects, were associated with lower pain intensity and milder knee-related symptoms. Our findings indicate that neuroinflammation in OA could be protective and associated with less severe symptoms.