Molecular and Cellular Mechanisms of Itch in Psoriasis
Abstract
:1. Introduction
2. Clinical Characteristic of Itch in Psoriasis
3. Itch Transmission Pathway
4. Pathophysiology of Itch in Psoriasis
4.1. The Nervous System
4.1.1. Neuropeptides
- (1)
- Substance P (SP)
- (2)
- Calcitonin Gene-Related Peptide (CGRP)
- (3)
- Neuropeptide Y (NPY)
4.1.2. Opioid Ligands and Their Receptors
4.1.3. TRP Cation Channel Subfamily (TRP Channels)
4.1.4. Nerve Growth Factor (NGF)
4.1.5. Sensory Nerve Fiber Density
4.2. The Immune System
4.2.1. Cytokines
- (1)
- Itch-Mediating Cytokines
- (1.1)
- Interleukin-31 (IL-31)
- (1.2)
- Thymic Stromal Lymphopoietin (TSLP)
- (1.3)
- IL-2
- (2)
- Cytokines Involved in the Pathogenesis of Psoriasis
- (2.1)
- IL-17
- (2.2)
- IL-22
- (2.3)
- IL-23
- (2.4)
- IL-26
4.2.2. Mast Cells and Gamma-Amino Butyric Acid (GABA)-Expressing Inflammatory Cells
4.2.3. Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) Pathway
4.3. The Endocrine System
4.3.1. Corticotropin-Releasing Hormone (CRH)
4.3.2. α-Melanocyte-Stimulating Hormone (α-MSH)
4.4. The Vascular System
4.4.1. Vascular Endothelial Growth Factor (VEGF)
4.4.2. Prostaglandin E2 (PGE2)
4.4.3. Endothelin-1 (ET-1)
4.4.4. Cell Adhesion Molecules
4.5. Epidermal Keratinocytes
4.6. Others
4.6.1. Dipeptidyl Peptidase IV (DPPIV, CD26)
4.6.2. Lipocalin-2 (LCN2)
5. Ongoing and Future Trials
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
α-MSH | α-melanocyte-stimulating hormone |
CGRP | Calcitonin gene-related peptide |
CRH | Corticotropin-releasing hormone |
DPPIV | Dipeptidyl peptidase IV |
DRG | Dorsal root ganglion |
ET-1 | Endothelin-1 |
GRP | Gastrin-releasing peptide |
GABA | Gamma-amino butyric acid |
HPA | Hypothalamic-pituitary-adrenal |
IL | Interleukin |
JAK | Janus kinase |
LCN2 | Lipocalin-2 |
KOR | κ-opioid receptor |
MC1R | Melanocortin 1 receptor |
MC5R | Melanocortin 5 receptor |
MOR | μ-opioid receptor |
Mrgpr | Mas-related G protein-coupled receptor |
NGF | Nerve growth factor |
NK-1R | Neurokinin-1 receptor |
NPY | Neuropeptide Y |
OSMR | Oncostatin M receptor |
p75 | p75 neurotrophin receptor |
PGA | Physician’s Global Assessment |
PGE2 | Prostaglandin E2 |
SP | Substance P |
STAT | Signal transducer and activator of transcription |
TrkA | Tropomyosin-receptor kinase A |
TRP | Transient receptor potential |
TRPA | Transient receptor potential ankyrin |
TRPC | Transient receptor potential canonical |
TRPM | Transient receptor potential melastatin |
TRPV | Transient receptor potential vanilloid |
TSLP | Thymic stromal lymphoprotein |
Th | T helper type |
VAP-1 | Vascular adhesion protein 1 |
VAS | Visual Analog Scale |
VEGF | Vascular endothelial growth factor |
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System | Category | Mediator | Expression Changes in the Mediator | Mechanisms (Such as Receptors) | Expression Changes in Receptors of the Mediator | Predictive Effects on Itch |
---|---|---|---|---|---|---|
Nervous | Neuropeptides | SP | ↑ (L [35], B [36]) | NK-1R | ↑ (L [7]) | Induction of itch [37,38] |
MrgprX2(Hu) | - | |||||
MrgprB2(Ms) | - | |||||
MrgprA1(Ms) | - | |||||
CGRP | ↑ (B [34]) | CGRPR | ↑ (B [7]) | Aggravation of itch? [39] | ||
NPY | ↓ (B [40]) | NPY1R | - | Suppression of mechanical itch [25] | ||
Opioids | β-endorphin | UC [41]/↑ (L [42]) | MOR | UC [41] | Induction of itch [43] | |
Dynorphin A | ↓ (L [41]) | KOR | ↓ (L [41]) | Suppression of itch [42,43] | ||
Neurotrophins | NGF | ↑ (L [35,44]) | TrkA | ↑ (L [35]) | NGF-TrkA axis: aggravation of histamine-independent itch [45] | |
P75 | - | |||||
Immune | Cytokines | IL-31 | ↑ (L [46], B [47]) | IL-31RA | - | Induction of itch [48] |
OSMRβ | - | |||||
TSLP | ↑ (L [49], B [50]) | TSLPR, | - | Induction of itch [51] | ||
IL-7Rα | - | |||||
IL-2 | ↑ (L [35]) | IL-2Rα | - | Induction of itch [52,53,54] | ||
IL-2Rβ | - | |||||
IL-2Rγ | - | |||||
IL-17 | ↑ (L [21]) | IL-17Rs | - | Enhancement of itch by altering perception? [55] | ||
IL-22 | ↑ (L [56]) | IL-22R1 | - | Enhancement of itch by activation of the GRP-GRPR signal? [57] | ||
IL-10R2 | - | |||||
IL-23 | ↑ (L [56,58]) | IL-23R | - | Enhancement of itch though the aggravation of inflammation? [59] | ||
IL-12Rβ1 | - | |||||
IL-26 | ↑ (L [60]) | Il-20R1 | - | Enhancement of itch by promoting the sensory neuronal development? [61] | ||
IL-10R2 | - | |||||
Endocrine | HPA axis | CRH | ↑ (L [62]) | CRHR1 | - | Induction/aggravation of itch by mast cell degranulation [63,64] |
α-MSH | ↑ (L [62]) | MC1R | - | Induction of itch [65,66] | ||
MC5R | ||||||
Vascular | Growth factors | VEGF | ↑ (L [67], B [68]) | VEGFRs | - | Aggravation of itch? [67] |
Prostanoids | PGE2 | ↑ (L [69]) | cAMP | - | Induction of weak itch and enhancement of histamine-/serotonin- induced itch [70,71] | |
Autacoids | ET-1 | ↑ (L [72]) | ET-A/ET-B | - | Induction of itch [73] | |
Cell adhesion molecules | E-selectin | ↑ (L [35]) | - | - | Aggravation of itch? | |
VAP-1 | ↑ (B [74]) | - | - | Aggravation of itch? | ||
Others | Peptidases | DPPIV | ↑ (L [36], B [75]) | SP (cleavage) | ↑ (L [35], B [36]) | Aggravation of itch [39,75] |
Lipocalins | LCN2 | ↑ (B [76]) | GRP (production) | - | Aggravation of itch [77] |
Category | Drug Name | Target Interaction | Phase | Administration Type | Significant Findings | NCT# | References |
---|---|---|---|---|---|---|---|
NK-1R inhibitor | Serlopitant | NK-1R | 2 | Oral | Yes | NCT03343639 | [158] |
TrkA inhibitor | CT327 | TrkA | 2b | Topical | Yes | NCT01465282 | [98] |
SNA-120 | 2b | Topical | No * | NCT03322137 | [159] | ||
PDE4 inhibitor | Apremilast | PDE4 | Scalp: 4 | Oral | - | NCT03553433 | [159,160] |
Plaque: 3 | Oral | Yes | NCT03721172 | ||||
OSMRβ moAb | KPL-716 | OSMRβ | Plaque: 2 (pilot study) | Injection | - | NCT03858634 | [161] |
IL-17 moAb | Secukinumab | IL-17A | 3 | SC | Yes | NCT01365455 | [110] |
3 | SC | Yes | NCT01358578 | [162] | |||
Ixekizumab | IL-17A | 3 | SC | Yes | NCT01597245 | [163] | |
3 (long-term test) | SC | Yes | NCT01474512 | [108] | |||
JAK inhibitor | Tofacitinib | JAK-STAT pathway | 3 | Oral | Yes | NCT01276639 | [164] |
Yes | NCT01309737 |
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Komiya, E.; Tominaga, M.; Kamata, Y.; Suga, Y.; Takamori, K. Molecular and Cellular Mechanisms of Itch in Psoriasis. Int. J. Mol. Sci. 2020, 21, 8406. https://doi.org/10.3390/ijms21218406
Komiya E, Tominaga M, Kamata Y, Suga Y, Takamori K. Molecular and Cellular Mechanisms of Itch in Psoriasis. International Journal of Molecular Sciences. 2020; 21(21):8406. https://doi.org/10.3390/ijms21218406
Chicago/Turabian StyleKomiya, Eriko, Mitsutoshi Tominaga, Yayoi Kamata, Yasushi Suga, and Kenji Takamori. 2020. "Molecular and Cellular Mechanisms of Itch in Psoriasis" International Journal of Molecular Sciences 21, no. 21: 8406. https://doi.org/10.3390/ijms21218406