In rat antigen-induced arthritis (AIA), a model of rheumatoid arthritis, a bilateral ED1⁺ cell invasion (macrophages) was observed in the lumbar dorsal root ganglia (DRG) at days 1-3 (Segond von Banchet et al., Pain 2009; 145:151-159). Macrophages are classified in three functional types, which develop in response to environmental stimuli. These are pro-inflammatory M1- and TNF-α induced macrophages, and anti-inflammatory M2-macrophages. In order to explore the putative functional relevance of macrophage invasion in DRGs on pain development in AIA, we characterised the macrophage type which invades the DRGs. Using specific antibodies for inducible NO synthase (iNOS), Arginase 1 (Arg1), Interleukin-6 (IL-6) and Cyclooxygenase-2 (Cox-2) we first tested the phenotype of isolated bone marrow derived macrophages. These were differentiated into the three subtypes by addition of either LPS/Interferon-γ (IFN-γ) (1 µg/ml// 10 nM), TNF-α (10 nM), or IL-4 (10 nM) for 24h. M1 macrophages (LPS/IFN-γ) expressed high levels of iNOS, IL-6 and Cox-2. TNF-α stimulated macrophages also expressed IL-6 and Cox-2, but at lower amounts, and they expressed Arg1 instead of iNOS. M2-macrophages (IL-4) expressed only Arg1. In DRG sections from AIA rats, ED1-positive macrophages showed colocalisation with IL-6 and Arg1. Thus the invaded macrophages appear to be TNF-α activated macrophages, consistent with the inhibition of macrophage invasion into the DRGs by TNF-α neutralization. Furthermore, they indicate that these macrophages do not kill neurons (this is dependent on the NO-producing M1 phenotype) consistent with the absence of ATF3 in DRGs. They may rather promote nociception by releasing IL-6. This is currently explored.