Role of the cysteine protease cathepsin S in neuropathic hyperalgesia.
Using a gene expression analysis approach we found that the mRNA encoding the lysosomal cysteine protease cathepsin S (CatS) was up-regulated in rat dorsal root ganglia (DRG) following peripheral nerve injury. CatS protein was expressed in infiltrating macrophages in DRG and near the site of injury. At both sites CatS expression progressively increased from day 3 to day 14 after injury. In naïve rats, intraplantar injection of activated rat recombinant (rr) CatS (0.3, 1 microg/rat) induced a mechanical hyperalgesia that developed within half-an-hour, diminished by 3h and was absent after 24h. Activated rrCathepsin B (CatB) and non-activated rrCatS injected intraplantarly at the same or higher doses than activated rrCatS had no effect on rat nociceptive thresholds. In nerve-injured rats, mechanical hyperalgesia, but not allodynia, was significantly reversed for up to 3h by systemic administration of a non-brain penetrant, irreversible CatS inhibitor (LHVS, 3-30 mg/kg s.c.). Depletion of peripheral macrophages by intravenous injection of liposome encapsulate clodronate (1ml, 5 mg/ml) partially reduced established mechanical hyperalgesia but not allodynia, and abolished the anti-hyperalgesic effect of LHVS. Our results demonstrate a pro-nociceptive effect of CatS and indicate that endogenous CatS released by peripheral macrophages contributes to the maintenance of neuropathic hyperalgesia following nerve injury.
Barclay
Jane
J
Novartis Institutes for Biomedical Research, 5 Gower Place, London WC1E 6BS, UK Department of Functional Genomics, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA Wolfson CARD, King's College London, Guy's Campus, London SE1 1UL, UK.
Clark
Anna K
AK
Ganju
Pam
P
Gentry
Clive
C
Patel
Sadhana
S
Wotherspoon
Glen
G
Buxton
Frank
F
Song
Chuanzheng
C
Ullah
Jakir
J
Winter
Janet
J
Fox
Alyson
A
Bevan
Stuart
S
Malcangio
Marzia
M
D000818:Animals; D002403:Cathepsins / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D002908:Chronic Disease; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic; D006930:Hyperalgesia / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology*; D008026:Ligation; D008264:Macrophages / Q000201:enzymology; D008297:Male; D009619:Nociceptors / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012584:Sciatic Nerve / Q000201:enzymology* / Q000276:immunology / Q000503:physiopathology; D012585:Sciatica / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology
D012333:RNA, Messenger; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C028217:cathepsin S