Macrophages play a crucial role in the pathogenesis of immune-mediated diseases such as rheumatoid arthritis. Activated macrophages produce reactive oxygen species like NO, matrix metallo-proteases and pro-inflammatory cytokines such as interleukin-6 (IL-6). All which have the potential to destroy own tissues. In a previous study (Segond von Banchet et al., Pain 2009;145:151–159) we detected a bilateral invasion of ED1+ cells (macrophages) in the lumbar dorsal root ganglia (DRG) of rats 3 days after an unilateral induction of antigen-induced arthritis (AIA) in the knee. At present the functional importance of this invasion is unknown because there is no evidence for damage of DRG neurons in the AIA model. In order to investigate whether macrophages and DRG neurons have the potential to interact we established an in vitro co-culture system of primary murine DRG neurons and bone marrow-derived macrophages. Isolated bone marrow cells were differentiated for 7 days with M-CSF and characterized by the markers CD68 (96%) and CD11b (75%). Cells stimulated with interferon-g (10 nmol/l) and LPS (100 ng/ml) showed an increased F4/80 expression (7.7% to 35.9%). Stimulated macrophages (for 24 hours) produced IL-6 (2.8 ng/ml) and NO (28.3 mmol/l). Unexpectedly, the production of both mediators was significantly reduced (IL6 to 2 ng/ml; NO to 12 mmol/l) when macrophages were co-cultured with DRG neurons. These data suggest that DRG neurons have the potential to inhibit, presumably by release of an inhibitory compound, the mediator production of activated macrophages which may protect them from being damaged.