The major role of macrophages and their product tumor necrosis factor alpha in the induction of arthritis triggered by bacterial DNA containing CpG motifs

Abstract

Objective: To understand the mechanisms of arthritis triggered by CpG-containing oligonucleotides (ODN).

Methods: Following the induction of CpG ODN-triggered arthritis in mice, we analyzed the impact of depletion of immune cells, including neutrophils, natural killer (NK) cells, and monocyte/macrophages, on the arthritis, as well as the impact in SCID mice lacking T and B cells. In addition, tumor necrosis factor alpha (TNFalpha) knockout mice were studied, and intraarticular administration of p65 antisense to nuclear factor kappaB (NF-kappaB) was used to examine effects in CpG ODN-triggered arthritis. Cytokine messenger RNA expression in synovial tissue was evaluated by in situ hybridization.

Results: The presence of macrophages was mandatory for the mediation of arthritis triggered by CpG ODN, whereas the absence of neutrophils, NK cells, T cells, and B cells was of minor importance in this regard. The proinflammatory cytokines TNFalpha, interleukin-1beta, and interleukin-12, which originate from macrophages, were frequently found in the inflamed joints, and TNFalpha was confirmed to be an important mediator in the development of arthritis, since the incidence and severity of joint inflammation were markedly reduced in TNFalpha knockout mice. NF-kappaB exerted an important regulatory role in the development of CpG ODN-mediated arthritis, since local administration of antisense to the p65 subunit of NF-kappaB diminished the incidence of inflammation by 50%.

Conclusion: Macrophages and their products play an important role in the development of arthritis triggered by bacterial DNA containing CpG motifs.