Expression of Substance P Receptors in Normal and Psoriatic Skin

Staniek, V; Doutremepuich, Jean-Daniel; Schmitt, Daniel; Claudy, A; Miséry, Laurent

doi:10.1159/000028051

Cited by 34 publications

(22 citation statements)

References 22 publications

(26 reference statements)

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“…Use of biotinylated SP suggested that NK-1 expression may be increased in keratinocytes from psoriatic plaques (71). Another study showed mast cells express the NK-1 receptor in both affected and unaffected psoriatic skin (6).…”

Section: Discussionmentioning

confidence: 99%

IL-33 augments substance P–induced VEGF secretion from human mast cells and is increased in psoriatic skin

Theoharides

Zhang²,

Kempuraj³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

295

272

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The peptide substance P (SP) has been implicated in inflammatory conditions, such as psoriasis, where mast cells and VEGF are increased. A relationship between SP and VEGF has not been well studied, nor has any interaction with the proinflammatory cytokines, especially IL-33. Here we report that SP (0.1-10 μM) induces gene expression and secretion of VEGF from human LAD2 mast cells and human umbilical core blood-derived cultured mast cells (hCBMCs). This effect is significantly increased by coadministration of IL-33 (5-100 ng/mL) in both cell types. The effect of SP on VEGF release is inhibited by treatment with the NK-1 receptor antagonist 733,060. SP rapidly increases cytosolic calcium, and so does IL-33 to a smaller extent; the addition of IL-33 augments the calcium increase. SP-induced VEGF production involves calcium-dependent PKC isoforms, as well as the ERK and JNK MAPKs. Gene expression of IL-33 and histidine decarboxylase (HDC), an indicator of mast cell presence/activation, is significantly increased in affected and unaffected (at least 15 cm away from the lesion) psoriatic skin, as compared with normal control skin. Immunohistochemistry indicates that IL-33 is associated with endothelial cells in both the unaffected and affected sites, but is stronger and also associated with immune cells in the affected site. These results imply that functional interactions among SP, IL-33, and mast cells leading to VEGF release contribute to inflammatory conditions, such as the psoriasis, a nonallergic hyperproliferative skin inflammatory disorder with a neurogenic component.inflammation | cytokines | IL-1 | innate immunity | stress

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Section: Discussionmentioning

confidence: 99%

IL-33 augments substance P–induced VEGF secretion from human mast cells and is increased in psoriatic skin

Theoharides

Zhang²,

Kempuraj³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

295

272

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“…Keratinocytes express receptors for SP (neurokinin 1) and CGRP (CRLR, RAMP1 and RAMP2)(10,30–32), and previous reports have provided data demonstrating that epidermal and other types of epithelial cells produce IL-1β in response to neuropeptide stimulation (33). Moreover, we had previously demonstrated that in vivo direct application of SP to mouse hindpaw skin results in an increased production of IL-1β (3).…”

Section: Discussionmentioning

confidence: 99%

Neuropeptides Contribute to Peripheral Nociceptive Sensitization by Regulating Interleukin-1β Production in Keratinocytes

Shi

Wang

et al. 2011

Anesthesia &Amp; Analgesia

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Background It is increasingly evident that there is a close connection between the generation of cutaneous inflammatory cytokines and elevated neuropeptide signaling in complex regional pain syndrome (CRPS) patients. Previously we observed in the rat tibia fracture model of CRPS that activation of caspase-1 containing NALP1 inflammasomes was required for interleukin (IL)-1β production in keratinocytes, and that administration of an IL-1 receptor antagonist (anakinra) reduced the fracture-induced hindpaw mechanical allodynia. We therefore hypothesized that neuropeptides lead to nociceptive sensitization through activation of the skin’s innate immune system by enhancing inflammasome expression and caspase-1 activity. Methods We determined whether the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) require IL-1β in order to support nociceptive sensitization when injected into mouse hindpaw skin by testing mechanical allodynia. We then investigated whether these neuropeptides could stimulate production of IL-1β in a keratinocyte cell line (REKs), and could increase the expression of inflammasome component proteins including NALP1 and caspase-1. Finally, we determined if neuropeptide-stimulated IL-1β production required activation of caspase-1 and cathepsin B. Results Intraplantar injections of SP and CGRP lead to allodynia in mouse hindpaws but CGRP was approximately 10-fold less potent in causing this response. Moreover, systemic administration of the IL-1 receptor (IL-1R) antagonist anakinra prevented sensitization after neuropeptide injection. Also, mouse skin keratinocytes express IL-1R which is up-regulated after local neuropeptide application. In vitro data demonstrated that both SP and CGRP increased IL-1β gene and protein expression in REKs in a dose-dependent manner. Furthermore, SP time- and dose-dependently up-regulated NALP1 and caspase-1 mRNA and protein levels in REKs. In contrast, CGRP time- and dose-dependently enhanced NALP1 and caspase-1 mRNA levels without causing a significant change in NALP1 or caspase-1 protein expression in REKs. Inhibition of caspase-1 activity using the selective inhibitor Ac-YVAD-CHO reduced SP and, less effectively, CGRP induced increases in IL-1β production in REK cells. The selective cathepsin B inhibitor CA-74Me inhibited neuropeptide induced IL-1β production in REKs as well. Conclusions Collectively, these results demonstrate that neuropeptides induce nociceptive sensitization by enhancing IL-1 β production in keratinocytes. Neuropeptides rely on both caspase-1 and cathepsin B for this enhanced production. Neuro-cutaneous signaling involving neuropeptide activation of the innate immunity may contribute to pain in CRPS patients.

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“…In the skin, there are several NK 1 receptor-expressing cells, including keratinocytes, 18,20,21) Langerhans cells, 22) endothelial cells, 23) macrophages, 24) the sensory nerve terminal, 25) and mast cell. 26) It is worth to examine which cells would be affected by repeated administration of Unseiin.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Effect of the Repeated Treatment with Unsei-in on Substance P-Induced Itch-Associated Responses through the Downregulation of the Expression of NK1 Tachykinin Receptor in Mice

Andoh

Honma

Kawaharada

et al. 2003

Biological & Pharmaceutical Bulletin

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Unsei-in, a traditional medicine, is prescribed against pruritic cutaneous diseases, but the mechanisms of antipruritic action are still unknown. In the present study, we examined the antipruritic effects of Unsei-in in mice. Single administration of Unsei-in did not inhibit substance P-induced itch-associated response (scratching) in mice. However, repeated treatment with Unsei-in for 7 d significantly inhibited substance P-induced scratching. The same repeated treatment with Unsei-in suppressed the expression of NK(1) tachykinin receptors in the skin. These results suggest that Unsei-in inhibits substance P-associated itching and that the inhibition is at least partly due to the suppression of the expression of NK(1) tachykinin receptors in the skin.

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Expression of Substance P Receptors in Normal and Psoriatic Skin

Cited by 34 publications

References 22 publications

IL-33 augments substance P–induced VEGF secretion from human mast cells and is increased in psoriatic skin

IL-33 augments substance P–induced VEGF secretion from human mast cells and is increased in psoriatic skin

Neuropeptides Contribute to Peripheral Nociceptive Sensitization by Regulating Interleukin-1β Production in Keratinocytes

Inhibitory Effect of the Repeated Treatment with Unsei-in on Substance P-Induced Itch-Associated Responses through the Downregulation of the Expression of NK1 Tachykinin Receptor in Mice

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