Effects of differently activated rodent macrophages on sensory neurons. Implications for arthritic pain.

Objective In arthritis, macrophages invade the affected joint. Experimental arthritis models have shown that macrophages also invade the dorsal root ganglia (DRGs) of the inflamed segments in which the perikarya of sensory neurons are located. It is unclear whether this macrophage invasion contributes to arthritis pain and/or furthers neuronal damage. The present study was undertaken to investigate how differently activated macrophages affect DRG neurons. Methods We determined the phenotype of macrophages in the DRGs of rats with antigen-induced arthritis (AIA). In a DRG neuron-macrophage coculture system, we investigated whether differently activated macrophages (stimulated with either lipopolysaccharide [LPS]/interferon-gamma [IFN gamma], tumor necrosis factor [TNF], or interleukin-4) damage DRG neurons and/or stimulate them to release the mediator calcitonin gene-related peptide (CGRP), which promotes pain and neurogenic inflammation. Results Macrophages in the DRGs of rats with AIA showed the phenotype of TNF-stimulated macrophages but did not express inducible nitric oxide synthase, which was found in cultured macrophages only after LPS/IFN activation. In neuron-macrophage cocultures, activation of macrophages stimulated DRG neurons to release CGRP within 1 hour, indicating neuronal activation by macrophages. Only 48-hour activation of macrophages with LPS/IFN increased the neuronal cell death rate in culture, provided that the macrophages were in direct contact with DRG neurons. This effect was dependent on nitric oxide. Conclusion Macrophages have the potential to stimulate sensory neurons in the DRGs, and this may contribute to arthritis pain. If they are classically activated, such as after LPS/IFN stimulation, this may also further neuronal cell death. This is not the case in AIA but may occur in models involving damage of sensory neurons.