Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

PNAS 104 (25): 10655-10660

Copyright © 2007 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / NEUROSCIENCE

Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain

Anna K. Clark*,{dagger}, Ping K. Yip{dagger}, John Grist{dagger}, Clive Gentry*, Amelia A. Staniland{dagger}, Fabien Marchand{dagger}, Maliheh Dehvari{dagger}, Glen Wotherspoon*, Janet Winter*, Jakir Ullah*,{ddagger}, Stuart Bevan*,§, and Marzia Malcangio*,{dagger},¶

*Novartis Institutes for Biomedical Research, 5 Gower Place, London WC1E 6BS, United Kingdom; and {dagger}Wolfson Centre for Age Related Diseases, King's College London, Guy's Campus, London SE1 1UL, United Kingdom

Edited by David Julius, University of California, San Francisco, CA, and approved April 25, 2007

Received for publication December 6, 2006.

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. Here, we report that in peripheral nerve-injured rats, the lysosomal cysteine protease cathepsin S (CatS) is critical for the maintenance of neuropathic pain and spinal microglia activation. After injury, CatS was exclusively expressed by activated microglia in the ipsilateral dorsal horn, where expression peaked at day 7, remaining high on day 14. Intrathecal delivery of an irreversible CatS inhibitor, morpholinurea-leucine-homophenylalanine-vinyl phenyl sulfone (LHVS), was antihyperalgesic and antiallodynic in neuropathic rats and attenuated spinal microglia activation. Consistent with a pronociceptive role of endogenous CatS, spinal intrathecal delivery of rat recombinant CatS (rrCatS) induced hyperalgesia and allodynia in naïve rats and activated p38 mitogen-activated protein kinase (MAPK) in spinal cord microglia. A bioinformatics approach revealed that the transmembrane chemokine fractalkine (FKN) is a potential substrate for CatS cleavage. We show that rrCatS incubation reduced the levels of cell-associated FKN in cultured sensory neurons and that a neutralizing antibody against FKN prevented both FKN- and CatS-induced allodynia, hyperalgesia, and p38 MAPK activation. Furthermore, rrCatS induced allodynia in wild-type but not CX3CR1-knockout mice. We suggest that 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 pronociceptive mediators.

Key Words: chemokines • microglia • proteases • allodynia • fractalkine

Author contributions: A.K.C., C.G., J.W., and M.M. designed research; A.K.C., P.K.Y., J.G., C.G., A.A.S., F.M., M.D., G.W., and J.U. performed research; A.K.C., P.K.Y., J.G., C.G., A.A.S., M.D., J.W., and M.M. analyzed data; and S.B. and M.M. wrote the paper.

{ddagger}Present address: Novartis Institutes for Biomedical Research, CH-4002 Basel, Switzerland.

§Present address: Wolfson Centre for Age Related Diseases, King's College London, Guy's Campus, London SE1 1UL, United Kingdom.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0610811104/DC1.

To whom correspondence should be sent at the {dagger} address. E-mail: marzia.malcangio{at}kcl.ac.uk

© 2007 by The National Academy of Sciences of the USA

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Fractalkine Signaling in Microglia Contributes to Ectopic Orofacial Pain following Trapezius Muscle Inflammation.
M. Kiyomoto, M. Shinoda, A. Okada-Ogawa, N. Noma, K. Shibuta, Y. Tsuboi, B. J. Sessle, Y. Imamura, and K. Iwata (2013)
J. Neurosci. 33, 7667-7680
   Abstract »    Full Text »    PDF »
Active cathepsins B, L, and S in murine and human pancreatitis.
V. Lyo, F. Cattaruzza, T. N. Kim, A. W. Walker, M. Paulick, D. Cox, J. Cloyd, J. Buxbaum, J. Ostroff, M. Bogyo, et al. (2012)
Am J Physiol Gastrointest Liver Physiol 303, G894-G903
   Abstract »    Full Text »    PDF »
Chronic-Pain-Associated Astrocytic Reaction in the Spinal Cord Dorsal Horn of Human Immunodeficiency Virus-Infected Patients.
Y. Shi, B. B. Gelman, J. G. Lisinicchia, and S.-J. Tang (2012)
J. Neurosci. 32, 10833-10840
   Abstract »    Full Text »    PDF »
CXCL5 Mediates UVB Irradiation-Induced Pain.
J. M. Dawes, M. Calvo, J. R. Perkins, K. J. Paterson, H. Kiesewetter, C. Hobbs, T. K. Y. Kaan, C. Orengo, D. L. H. Bennett, and S. B. McMahon (2011)
Science Translational Medicine 3, 90ra60
   Abstract »    Full Text »    PDF »
Neuregulin-ErbB Signaling Promotes Microglial Proliferation and Chemotaxis Contributing to Microgliosis and Pain after Peripheral Nerve Injury.
M. Calvo, N. Zhu, C. Tsantoulas, Z. Ma, J. Grist, J. A. Loeb, and D. L. H. Bennett (2010)
J. Neurosci. 30, 5437-5450
   Abstract »    Full Text »    PDF »
Interactions between Chemokines: REGULATION OF FRACTALKINE/CX3CL1 HOMEOSTASIS BY SDF/CXCL12 IN CORTICAL NEURONS.
A. Cook, R. Hippensteel, S. Shimizu, J. Nicolai, A. Fatatis, and O. Meucci (2010)
J. Biol. Chem. 285, 10563-10571
   Abstract »    Full Text »    PDF »
Proteomic Analysis Uncovers Novel Actions of the Neurosecretory Protein VGF in Nociceptive Processing.
M. S. Riedl, P. D. Braun, K. F. Kitto, S. A. Roiko, L. B. Anderson, C. N. Honda, C. A. Fairbanks, and L. Vulchanova (2009)
J. Neurosci. 29, 13377-13388
   Abstract »    Full Text »    PDF »
The Liberation of Fractalkine in the Dorsal Horn Requires Microglial Cathepsin S.
A. K. Clark, P. K. Yip, and M. Malcangio (2009)
J. Neurosci. 29, 6945-6954
   Abstract »    Full Text »    PDF »
Interleukin-18-Mediated Microglia/Astrocyte Interaction in the Spinal Cord Enhances Neuropathic Pain Processing after Nerve Injury.
K. Miyoshi, K. Obata, T. Kondo, H. Okamura, and K. Noguchi (2008)
J. Neurosci. 28, 12775-12787
   Abstract »    Full Text »    PDF »
Chemokine Action in the Nervous System.
R. J. Miller, W. Rostene, E. Apartis, G. Banisadr, K. Biber, E. D. Milligan, F. A. White, and J. Zhang (2008)
J. Neurosci. 28, 11792-11795
   Full Text »    PDF »
Crucial Role of CB2 Cannabinoid Receptor in the Regulation of Central Immune Responses during Neuropathic Pain.
I. Racz, X. Nadal, J. Alferink, J. E. Banos, J. Rehnelt, M. Martin, B. Pintado, A. Gutierrez-Adan, E. Sanguino, J. Manzanares, et al. (2008)
J. Neurosci. 28, 12125-12135
   Abstract »    Full Text »    PDF »
Interferon-{gamma} Is a Critical Modulator of CB2 Cannabinoid Receptor Signaling during Neuropathic Pain.
I. Racz, X. Nadal, J. Alferink, J. E. Banos, J. Rehnelt, M. Martin, B. Pintado, A. Gutierrez-Adan, E. Sanguino, N. Bellora, et al. (2008)
J. Neurosci. 28, 12136-12145
   Abstract »    Full Text »    PDF »
Chemokines and the pathophysiology of neuropathic pain.
F. A. White, H. Jung, and R. J. Miller (2007)
PNAS 104, 20151-20158
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882