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Synaptic Plasticity in Pain pp 455–471Cite as

The Cathepsin S/Fractalkine Pair: New Players in Spinal Cord Neuropathic Pain Mechanisms

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Abstract

A recent major conceptual advance has been the recognition of the importance of immune system-neuronal interactions in the modulation of brain function. One example of which is spinal pain processing in neuropathic states. Mounting evidence supports the hypothesis that pro-inflammatory mediators secreted by microglia modulate nociceptive function in the injured CNS and following peripheral nerve damage. Here we examine the evidence that one such mediator, the lysosomal cysteine protease cathepsin S (CatS), is critical for the maintenance of neuropathic pain and spinal microglia activation in neuropathic pain states. CatS exerts its pro-nociceptive effects via cleavage of the transmembrane chemokine fractalkine (FKN). Under conditions of increased nociception, microglial CatS is responsible for the liberation of neuronal FKN which stimulates p38 MAPK phosphorylation in microglia thereby activating neurons via the release of pro-nociceptive mediators, thus establishing a new role for the CatS/FKN pair in the maintenance of neuropathic hypersensitivity and suggest that CatS inhibition constitutes a novel therapeutic approach for the treatment of chronic pain.

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Abbreviations

CatS:

cathepsin S

FKN:

fractalkine

APCs:

antigen presenting cells

DCs:

dendritic cells

MHC:

major histocompatibility complex

Ii:

invariant chain

CLIP:

class II-associated Ii peptide

HLA-DM:

human leukocyte antigen DM

LHVS:

morpholinurea-leucine-homophenylalanine-vinyl sulfone-phenyl

PNL:

partial sciatic nerve ligation

CCI:

chronic constriction injury

SNL:

spinal nerve ligation

ADAM:

a disintegrin and metalloprotease domain

TACE:

tumour necrosis factor-α converting enzyme

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  1. Wolfson Centre for Age Related Diseases, King’s College London, Guy’s Campus, London, SE1 1UL, UK

    Anna K. Clark & Marzia Malcangio

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  1. Anna K. Clark
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  2. Marzia Malcangio
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Correspondence to Anna K. Clark .

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    Clark, A.K., Malcangio, M. (2009). The Cathepsin S/Fractalkine Pair: New Players in Spinal Cord Neuropathic Pain Mechanisms. In: Malcangio, M. (eds) Synaptic Plasticity in Pain. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-0226-9_22

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