Cathepsin S acts via protease-activated receptor 2 to activate sensory neurons and induce itch-like behaviour

Chung, Keshi; Pitcher, Thomas; Grant, Andrew; Hewitt, Ellen; Lindström, Erik; Malcangio, Marzia

doi:10.1016/j.ynpai.2019.100032

Cited by 25 publications

(24 citation statements)

References 42 publications

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“…Kallikreins (KLK) of the serine protease-family promote atopic CP, by inducing skin barrier dysfunction (KLK5), activating protease activate receptor (PAR)-2 receptors on keratinocytes or sensory neurons or via non-inflammatory mechanisms (KLK7) [ 18 , 19 ]. Cathepsin S, another epidermal cystein protease, is involved in both AD-related inflammation and in histamine-independent itch, by activating Mas-related G-protein-coupled receptors (Mrgprs) and PAR-2 on sensory neurons [ 20 , 21 ]. Furthermore, the multifunctional ECM protein periostin can directly activate primary sensory afferents, via its aVβ3 integrin receptor, in the skin, inducing itch in-vivo, as a pruritogen [ 22 ].…”

Section: Th2 Immunity As a Driver Of Chronic Pruritusmentioning

confidence: 99%

Pruritus as a Distinctive Feature of Type 2 Inflammation

et al. 2021

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Pruritus is a common symptom of several skin diseases, both inflammatory and neoplastic. Pruritus might have a tremendous impact on patients’ quality of life and strongly interfere with sleep, social, and work activities. We review the role of type-2 inflammation and immunity in the pathogenesis of chronic pruritic conditions of the skin. Type 2 cytokines, including IL-4, IL-13, thymic stromal lymphopoietin, periostin, IL-31, IL-25, and IL-33 are released by mast cells, innate lymphoid cells 2, keratinocytes, and type 2 T lymphocytes, and are master regulators of chronic itch. These cytokines might act as direct pruritogen on primary sensory neurons (pruriceptors) or alter the sensitivity to other itch mediators Type 2 inflammation- and immunity-dominated skin diseases, including atopic dermatitis, prurigo nodularis, bullous pemphigoid, scabies, parasitic diseases, urticaria, and Sézary syndrome are indeed conditions associated with most severe pruritus. In contrast, in other skin diseases, such as scleroderma, lupus erythematosus, hidradenitis suppurativa, and acne, type 2 inflammation is less represented, and pruritus is milder or variable. Th2 inflammation and immunity evolved to protect against parasites, and thus, the scratching response evoked by pruritus might have developed to alert about the presence and to remove parasites from the skin surface.

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Section: Th2 Immunity As a Driver Of Chronic Pruritusmentioning

confidence: 99%

Pruritus as a Distinctive Feature of Type 2 Inflammation

et al. 2021

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“…PAR2 is also expressed in KCs (Steinhoff et al, 1999). Among the endogenous PAR2activating proteases, cathepsin S (Cat-S) elicits itch in mice and humans (Chung et al, 2019;, is involved in neuropathic pain (Barclay et al, 2007;Clark et al, 2007) and is expressed by KCs (Schwarz et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

PAR2, Keratinocytes, and Cathepsin S Mediate the Sensory Effects of Ciguatoxins Responsible for Ciguatera Poisoning

L’Hérondelle

Pierre

Fouyet

et al. 2021

Journal of Investigative Dermatology

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“…As PbTxs are unlikely to exert direct protease activity, we hypothesized that PAR2 activation is indirectly induced by proteases, especially Cat-S in a Na v -dependent manner [ 29 , 81 ]. Cat-S activates PAR2 in vitro [ 34 ] and induces in vivo itch, pain and inflammation in a PAR2-dependent manner [ 53 , 56 , 82 ]. Moreover, Cat-S plays a major role in the microglial activation and maintenance of neuropathic and chronic pain [ 83 , 84 ].…”

Section: Discussionmentioning

confidence: 99%

Calcium Increase and Substance P Release Induced by the Neurotoxin Brevetoxin-1 in Sensory Neurons: Involvement of PAR2 Activation through Both Cathepsin S and Canonical Signaling

Pierre¹,

Fouchard

Buscaglia

et al. 2020

Cells

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Red tides involving Karenia brevis expose humans to brevetoxins (PbTxs). Oral exposition triggers neurotoxic shellfish poisoning, whereas inhalation induces a respiratory syndrome and sensory disturbances. No curative treatment is available and the pathophysiology is not fully elucidated. Protease-activated receptor 2 (PAR2), cathepsin S (Cat-S) and substance P (SP) release are crucial mediators of the sensory effects of ciguatoxins (CTXs) which are PbTx analogs. This work explored the role of PAR2 and Cat-S in PbTx-1-induced sensory effects and deciphered the signaling pathway involved. We performed calcium imaging, PAR2 immunolocalization and SP release experiments in monocultured sensory neurons or co-cultured with keratinocytes treated with PbTx-1 or P-CTX-2. We demonstrated that PbTx-1-induced calcium increase and SP release involved Cat-S, PAR2 and transient receptor potential vanilloid 4 (TRPV4). The PbTx-1-induced signaling pathway included protein kinase A (PKA) and TRPV4, which are compatible with the PAR2 biased signaling induced by Cat-S. Internalization of PAR2 and protein kinase C (PKC), inositol triphosphate receptor and TRPV4 activation evoked by PbTx-1 are compatible with the PAR2 canonical signaling. Our results suggest that PbTx-1-induced sensory disturbances involve the PAR2-TRPV4 pathway. We identified PAR2, Cat-S, PKA, and PKC that are involved in TRPV4 sensitization induced by PbTx-1 in sensory neurons.

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Cathepsin S acts via protease-activated receptor 2 to activate sensory neurons and induce itch-like behaviour

Cited by 25 publications

References 42 publications

Pruritus as a Distinctive Feature of Type 2 Inflammation

Pruritus as a Distinctive Feature of Type 2 Inflammation

PAR2, Keratinocytes, and Cathepsin S Mediate the Sensory Effects of Ciguatoxins Responsible for Ciguatera Poisoning

Calcium Increase and Substance P Release Induced by the Neurotoxin Brevetoxin-1 in Sensory Neurons: Involvement of PAR2 Activation through Both Cathepsin S and Canonical Signaling

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