Peripheral Role of Cathepsin S in Th1 Cell-Dependent Transition of Nerve Injury-Induced Acute Pain to a Chronic Pain State

We have read with interest this article by the Nakanishi group, which provides evidence for a role of peripheral Cathepsin S in the generation of neuropathic pain. We are pleased to note that this study confirmed our observations as indeed we were the first authors to report on the therapeutic potential of peripheral and central CatS inhibition for the treatment of neuropathic pain (Barclay et al., 2007; Clark et al., 2007; Irie et al., 2008). We provided evidence for an extracellular role of CatS located in macrophages (periphery) and microglia (centrally) in the maintenance of neuropathic pain. This article supports our suggestion that CatS is critical for neuropathic pain maintenance, because in figure 1a of Zhang and colleagues article, CatS knockout mice develop the same degree of allodynia as wild-type mice 1 and 2 days after injury. Likewise, in figure 1b when the CatS antagonist ZFL is administered by daily injections commencing on day 0 after injury a total of 5 days are required to start reversing allodynia, which is in line with a lack of participation in the initiation of neuropathic pain that we have previously demonstrated.

We are surprised that our work is discussed as being in contrast with this study and that reference to our study on peripheral CatS in macrophages is missed. Nevertheless, in addition to the role of extracellular CatS during neuropathic pain demonstrated by our group, this elegant study demonstrates yet another site of action for CatS inhibitors in the periphery: that intracellular CatS in the dendritic cells of the spleen contribute to neuropathic pain via the classical role for CatS in antigen presentation.

References

Barclay J, Clark AK, Ganju P, Gentry C, Patel S, Wotherspoon G, Buxton F, Song C, Ullah J, Winter J, Fox A, Bevan S, Malcangio M. Role of the cysteine protease cathepsin S in neuropathic hyperalgesia. Pain, 130:225-234, 2007.

Clark AK, Yip P, Grist J, Gentry C, Staniland AA, Marchand F, Dehvari M, Wotherspoon G, Winter J, Ullah J, Bevan SB, Malcangio M. Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain. Proc. Natl. Acad. Sci. USA, 104:10655-10660, 2007. Please note that this paper is discussed in the Zhang article.

Irie O, Kosaka T, Ehara T, Yokokawa F, Kanazawa T, Hirao H, Iwasaki A, Sakaki J, Teno N, Hitomi Y, Iwasaki G, Fukaya H, Nonomura K, Tanabe K, Koizumi S, Uchiyama N, Bevan SJ, Malcangio M, Gentry C, Fox AJ, Yaqoob M, Culshaw AJ, Hallett A.Discovery of Orally Bioavailable Cathepsin S Inhibitors for the Reversal of Neuropathic Pain. J. Med .Chem. 51: 5502-5505,2008.

Conflict of Interest:

None declared