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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Invest Dermatol. Author manuscript; available in PMC 2010 May 1.
Published in final edited form as:
PMCID: PMC2855395

Cathepsin S elicits itch and signals via protease-activated receptors

To the Editor

Cathepsin S is a cysteine protease linked to inflammatory processes including atherosclerosis and asthma. The possibility that this or other cysteine proteases might evoke itch or be part of a classical ligand-receptor signaling cascade has not been considered previously. We show here that human cathepsin S evokes itch and activates human protease-activated receptors 2 and 4.

The sensation of itch is mediated by two distinct non-overlapping populations of cutaneous nerve fibers that evoke comparable degrees of itch (Namer et al., 2008; Johanek et al., 2008). One set of fibers, the mechano-insensitive population, is more responsive to histamine than to cowhage. The other set is mechanosensitive and is more responsive to cowhage than to histamine (Namer et al., 2008; Johanek et al., 2008). Histamine is a classical mediator of itch and is associated with a wheal and flare. Since most clinical itches do not have a wheal or flare and do not respond to antihistamines, histamine is not thought to contribute to most itches (Ikoma et al., 2006). Cowhage refers to a tropical legume or, in this case, the loose hairs that cover the pods of Mucuna pruriens, and evoke itch. The active component of cowhage is mucunain, a cysteine protease that serves as a ligand for protease-activated receptors (PARs) 2 and 4 (Reddy et al., 2008). The identification of an endogenous mediator with properties similar to cowhage could lead to insights into non-histamine mediated itch. We focused on human cathepsin S because it shares active site sequence homology with mucunain and is selectively up-regulated in human keratinocytes upon stimulation with interferon-gamma, consistent with a possible pruritic role in inflammatory skin disease (Schwarz et al., 2002).

There are fifteen human cathepsins, including eleven cysteine, two aspartic and two serine proteases. Cathepsins were traditionally considered lysosomal proteases. It is now recognized that the broad expression and range of pH dependence of some cathepsins reveal that they have many functional roles including tissue remodeling, metastasis and inflammation. Examples of cysteine cathepsin activities include cleavage of collagen by cathepsin L to generate endostatin (Felbor et al. 2000), an endogenous inhibitor of angiogenesis, and cleavage of the invariant chain in antigen presenting cells by cathepsin S (Nakagawa et al., 1999) as part of the inflammatory cascade.

There are four PARs and they are members of the G-protein coupled receptor family. Their identified endogenous activators are all serine proteases. These proteases trigger the activation of PARs by unmasking ‘tethered ligand’ sequences near the N-termini of the receptors. Certain kallikrein-related peptidases and mast cell tryptase, which are serine proteases, can activate PAR2 in vitro (Oikonomopoulou et al., 2006, Stefansson et al., 2008) but they have not been demonstrated to be endogenous pruritic agents. Serine proteases and PAR2 have also been linked to barrier function (Hachem et al., 2006). The presence of PAR2 on free nerve endings in the skin, keratinocytes and dorsal root ganglia link this receptor to itch and pain (Steinhoff et al., 2000, Steinhoff et al., 2003, and Shpacovitch et al., 2008). Data on PAR4 are more limited, revealing that it is expressed in rat dorsal root ganglia and its activation, at least in this species, appears to be antinociceptive (Asfaha et al., 2007). A PAR4 hexapeptide agonist has recently been reported to cause scratching in mice (Tsujii et al., 2008).

Cathepsin S and mucunain are endogenous and exogenous cysteine proteases, evoke similar itch and nociceptive sensations, and serve to activate PAR-2 and 4 (Figure 1, Figure 2 and Reddy et al., 2008). The relative contribution of PAR2 versus PAR4 activation in cathepsin S-induced sensations is not addressed by these data. Cathepsin S has been implicated in neuropathic pain, manifest by increased gene expression in rat dorsal root ganglia following peripheral nerve injury. Such pain was lessened by a cathepsin S inhibitor (Barclay et al., 2007). These observations suggest that cathepsin S may have an excitatory effect on neurons. As keratinocytes have been demonstrated to express cathepsin S (Schwarz et al., 2002), a role for this protease in keratinocyte-neuronal communication may be expected. Cathepsin S may contribute to the pruritus of inflammatory skin conditions including atopic dermatitis and psoriasis and could have a role in barrier function. Cathepsin S and other endogenous or exogenous cysteine proteases may activate PARs as part of additional inflammatory processes. For example, Der p1, a mite cysteine protease associated with asthma activates PAR2 (Asokananthan et al., 2002). Taken together, we suggest that exogenous and endogenous cysteine proteases interact with PARs as part of signaling cascades in homeostasis and disease.

Figure 1
Recombinant human cathepsin S evokes itch. (a) Mean perceived intensity of itch, pricking/stinging and burning sensations evoked by a single inactivated spicule reconstituted with cathepsin S. Briefly, spicules were inactivated by autoclaving and then ...
Figure 2
Recombinant human cathepsin S activates human PARs. (a) Single cell imaging of cathepsin S (2 µM) induced responses in HeLa cells transfected with either PAR 2 or PAR 4 as measured by ratiometric calcium imaging in cells loaded with fura-2 as ...

Supplementary Material

Supplemental Material


This work was supported in part by a Clinical and Translational Science Award, National Center for Research Resources (NCRR) Grant UL1 RR0249139 [a component of the National Institutes of Health (NIH)], NIH Grant P01 NS047300 (R.H.L., PI), and an agreement between Massachusetts General Hospital and The Shiseido Co. Ltd. (Tokyo, Japan). Psychophysical experiments were approved by the Yale University Human Investigation Committee. The study was conducted according to Declaration of Helsinki Principles. Participants gave their written informed consent. We thank Aurel Iuga, and Barry Green for their input and technical assistance.


protease-activated receptor


Conflict of Interest

The authors declare no conflict of interest.


  • Asfaha S, Cenac N, Houle S, Altier C, Papez MD, Nguyen C, Steinhoff M, Chapman K, Zamponi GW, Vergnolle N. Protease-activated receptor-4: a novel mechanism of inflammatory pain modulation. Brit J Pharmacol. 2007;150:176–185. [PMC free article] [PubMed]
  • Asokananthan N, Graham PT, Stewart DJ, Bakker AJ, Eidne KA, Thompson PJ, Stewart GA. House dust mite allergens induce pro-inflammatory cytokines from respiratory epithelial cells: the cysteine protease allergen, Der p 1, activates protease-activated receptor (PAR)-2 and inactivates PAR-1. J Immunol. 2002;169:4572–4578. [PubMed]
  • 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. 2007;130:225–234. [PubMed]
  • Felbor U, Dreier L, Bryant RA, Ploegh HL, Olsen BR, Mothes W. Secreted cathepsin L generates endostatin from collagen XVIII. EMBO J. 2000;19:1187–1194. [PubMed]
  • Hachem JP, Houben E, Crumrine D, Man MQ, Schurer N, Roelandt T, Choi EH, Uchida Y, Brown BE, Feingold KR, Elias PM. Serine protease signaling of epidermal permeability barrier homeostasis. J Invest Dermatol. 2006;126:2074–2086. [PubMed]
  • Ikoma A, Steinhoff M, Ständer S, Yosipovitch G, Schmelz M. The neurobiology of itch. Nat Rev Neurosci. 2006;7:535–547. [PubMed]
  • Johanek LM, Meyer RA, Friedman RM, Greenquist KW, Shim B, Borzan J, Hartke T, LaMotte RH, Ringkamp M. A role for polymodal C-fiber afferents in nonhistaminergic itch. J Neurosci. 2008;28:7659–7669. [PMC free article] [PubMed]
  • Nakagawa TY, Brissette WH, Lira PD, Griffiths RJ, Petrushova N, Stock J, McNeish JD, Eastman SE, Howard ED, Clarke SR, Rosloniec EF, Elliott EA, Rudensky AY. Impaired invariant chain degradation and antigen presentation and diminished collagen-induced arthritis in cathepsin S null mice. Immunity. 1999;10:207–217. [PubMed]
  • Namer B, Carr R, Johanek LM, Schmelz M, Handwerker HO, Ringkamp M. Separate peripheral pathways for pruritus in man. J Neurophysiol. 2008;100:2062–2069. [PubMed]
  • Oikonomopoulou K, Hansen KK, Saifeddine M, Vergnolle N, Tea I, Blaber M, Blaber SI, Scarisbrick I, Diamandis EP, Hollenberg MD. Kallikrein-mediated cell signalling: targeting proteinase-activated receptors (PARs) Biol. Chem. 2006;387:817–824. [PubMed]
  • Reddy VB, Iuga AO, Shimada S, LaMotte RH, Lerner EA. Cowhage evoked itch is mediated by a novel cysteine protease - a ligand of protease activated receptors. J Neurosci. 2008;28:4331–4335. [PMC free article] [PubMed]
  • Schwarz G, Boehncke WH, Braun M, Schroter CJ, Burster T, Flad T, Dressel D, Weber E, Schmid H, Kalbacher H. Cathepsin S activity is detectable in human keratinocytes and is selectively upregulated upon stimulation with interferon-γ J Invest Dermatol. 2002;119:44–49. [PubMed]
  • Shpacovitch V, Feld M, Hollenberg MD, Luger TA, Steinhoff M. Role of protease-activated receptors in inflammatory responses, innate and adaptive immunity. J Leukoc Biol. 2008;83:1309–1322. [PubMed]
  • Stefansson K, Brattsand M, Roosterman D, Kempkes C, Bocheva G, Steinhoff M, Egelrud T. Activation of proteinase-activated receptor-2 by human kallikrein-related peptidases. J Invest Dermatol. 2008;128:18–25. [PubMed]
  • Steinhoff M, Vergnolle N, Young SH, Tognetto M, Amadesi S, Ennes HS, Trevisani M, Hollenberg MD, Wallace JL, Caughey GH, Mitchell SE, Williams LM, Geppetti P, Mayer EA, Bunnett NW. Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechnism. Nat Med. 2000;6:151–158. [PubMed]
  • Steinhoff M, Neisius U, Ikoma A, Fartasch M, Heyer G, Skov PS, Luger TA, Schmelz M. Proteinase-activated receptor 2 mediates itch: a novel pathway for pruritus in human skin. J Neurosci. 2003;23:6176–6180. [PubMed]
  • Tsujii K, Andoh T, Lee JB, Kuraishi Y. Activation of proteinase-activated receptors induces itch-associated responses through histamine-dependent and independent pathways in mice. J Pharmacol Sci. 2008;108:385–388. [PubMed]