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The Journal of Neuroscience, May 27, 2009, 29(21):6945-6954; doi:10.1523/JNEUROSCI.0828-09.2009

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Development/Plasticity/Repair
The Liberation of Fractalkine in the Dorsal Horn Requires Microglial Cathepsin S

Anna K. Clark, Ping K. Yip, and Marzia Malcangio

Wolfson Centre for Age Related Diseases, King's College London, Guy's Campus, London SE1 1UL, United Kingdom

Correspondence should be addressed to Dr. Anna K. Clark, Wolfson Centre for Age Related Diseases, Kings College London, Wolfson Wing, Hodgkin Building, Guy's Campus, London SE1 1UL, UK. Email: anna.clark{at}kcl.ac.uk

Understanding of the sequence and nature of the events that govern neuron–microglia communication is critical for the discovery of new mechanisms and targets for chronic pain treatment. The neuronal chemokine fractalkine (FKN) and its microglial receptor CX3CR1 may mediate such a function in the dorsal horn of the spinal cord after cleavage of the extracellular domain of this transmembrane chemokine by a protease. Here we report that in neuropathic rat dorsal horn, with dorsal root-attached preparations, soluble FKN (sFKN) contents are increased in the superfusates collected after noxious-like electrical stimulation of ipsilateral primary afferent fibers. The increase of sFKN is prevented by morpholinurea-leucine-homophenylalanine-vinyl sulfone-phenyl (LHVS), an irreversible inhibitor of cathepsin S (CatS) whose proteolytic activity is also increased in the superfusates. The source of CatS activity is microglial cells activated by the peripheral nerve injury and secreting the enzyme, as a result of primary afferent fiber stimulation. Indeed, the acute activation of dorsal horn microglia by lipopolysaccharide results in increased CatS activity in the superfusates, followed by increased sFKN contents. Consistent with these observations ex vivo, the levels of both sFKN and CatS activity in CSF samples increased significantly after peripheral nerve injury, associated with spinal microglial activation. Finally, because we found that both FKN immunoreactivity and mRNA are confined to dorsal horn neurons, we suggest that under neuropathic conditions, noxious stimulation of primary afferent fibers induces release of CatS from microglia, which liberates FKN from dorsal horn neurons, thereby contributing to the amplification and maintenance of chronic pain.

Received Feb. 18, 2009; revised March 24, 2009; accepted April 28, 2009.

Correspondence should be addressed to Dr. Anna K. Clark, Wolfson Centre for Age Related Diseases, Kings College London, Wolfson Wing, Hodgkin Building, Guy's Campus, London SE1 1UL, UK. Email: anna.clark{at}kcl.ac.uk






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