2019.05.03

: Filename : zhou2018.pdf (507 KB)
Caption : https://doi.org/10.1016/j.jdermsci.2018.11.009

2018 Dec;92(3):264-271. doi: 10.1016/j.jdermsci.2018.11.009. Epub 2018 Nov 26.

TRPV1 mediates inflammation and hyperplasia in imiquimod (IMQ)-induced psoriasiform dermatitis (PsD) in mice.

Zhou Y¹, Follansbee T², Wu X³, Han D¹, Yu S³, Domocos DT², Shi Z³, Carstens M², Carstens E², Hwang ST⁴.

Abstract

BACKGROUND:

Transient Receptor Potential Vanilloid 1 (TRPV1) is known to mediate itch and neurogenic inflammation, but the role of TRPV1 in psoriasiform dermal inflammation is poorly understood.

OBJECTIVE:

To investigate the function of TRPV1 in imiquimod (IMQ)-induced psoriasiform dermatitis (PsD) in mice.

METHODS:

Following daily treatment of topical IMQ cream for consecutive 5 days in C57BL/6 wide-type (WT) and TRPV1 gene knockout (KO) mice, we assessed the psoriasis severity index (PSI) scores, transepidermal water loss (TEWL), dermal inflammatory infiltrates, as well as gene expression levels for psoriasis related genes in mouse skin lesions.

RESULTS:

Compared with WT mice, the clinical and TEWL scores, the extent of skin hyperplasia, the area of Munro microabscesses (MM) and angiogenesis of psoriasis were all significantly decreased in TRPV1 KO mice triggered with IMQ, suggesting a reduction in skin inflammation and barrier defects. In addition, the infiltration of CD45⁺ leukocytes, mast cells as well as CD3⁺ T cells was all reduced in the IMQ-treated skin of TRPV1 KO mice. Quantitative Real-time PCR (RT-qPCR) revealed that expression levels of IL-1β, IL-6, IL-23, S100A8 were decreased while IL-10 was increased in TRPV1 KO mice.

CONCLUSIONS:

In summary, key markers of psoriatic inflammation and epidermal hyperplasia are reduced in TRPV1 KO mice, indicating the involvement of TRPV1 in the psoriasiform inflammation and suggesting its potential as a therapeutic target.

KEYWORDS:

Itch; Pain neuroinflammation; Psoriasis

PMID:: 30527377
DOI:: 10.1016/j.jdermsci.2018.11.009

2019.05.03 Read More »

2019.04.12

Babina Sanjel

Nppb Neurons Are Sensors of Mast Cell-Induced Itch.

Solinski HJ¹, Kriegbaum MC¹, Tseng PY¹, Earnest TW¹, Gu X¹, Barik A², Chesler AT², Hoon MA³.

Abstract

Itch is an unpleasant skin sensation that can be triggered by exposure to many chemicals, including those released by mast cells. The natriuretic polypeptide b (Nppb)-expressing class of sensory neurons, when activated, elicits scratching responses in mice, but it is unclear which itch-inducing agents stimulate these cells and the receptors involved. Here, we identify receptors expressed by Nppb neurons and demonstrate the functional importance of these receptors as sensors of endogenous pruritogens released by mast cells. Our search for receptors in Nppb neurons reveals that they express leukotriene, serotonin, and sphingosine-1-phosphate receptors. Targeted cell ablation, calcium imaging of primary sensory neurons, and conditional receptor knockout studies demonstrate that these receptors induce itch by the direct stimulation of Nppb neurons and neurotransmission through the canonical gastrin-releasing peptide (GRP)-dependent spinal cord itch pathway. Together, our results define a molecular and cellular pathway for mast cell-induced itch.

KEYWORDS: Cysltr2; Htr1f; Nppb; S1pr1; Trpv1; itch; mast cell

Nppb Neurons Are Sensors of Mast Cell-Induced Itc

Supplementary information-1

Supplementary information-2

2019.04.12 Read More »

2019.04.05

qhsl93

The Genetics of Chronic Itch: Gene Expression in the Skin of Patients with Atopic Dermatitis and Psoriasis with Severe Itch.

Abstract

To identify itch-related mediators and receptors that are differentially expressed in pruritic skin, we used RNA sequencing to analyze the complete transcriptome in skin from paired itchy, lesional and nonitchy, nonlesional skin biopsies from 25 patients with atopic dermatitis and 25 patients with psoriasis and site-matched biopsies from 30 healthy controls. This analysis identified 18,000 differentially expressed genes common between itchy atopic and psoriatic skin compared with healthy skin. Of those, almost 2,000 genes were differentially expressed between itchy and nonitchy skin in atopic and psoriatic subjects. Overexpression of several genes, such as phospholipase A2 IVD, substance P, voltage-gated sodium channel 1.7, and transient receptor potential (TRP) vanilloid 1, in itchy skin was positively correlated with itch intensity ratings in both atopic dermatitis and psoriasis. Cytokines such as IL-17A, IL-23A, and IL-31 had elevated gene transcript levels in both itchy atopic and psoriatic skin. However, expression of genes for TRP vanilloid 2, TRP ankyrin 1, protease-activated receptor 2, protease-activated receptor 4, and IL-10 was found to be increased only in pruritic atopic skin, whereas expression of genes for TRP melastatin 8, TRP vanilloid 3, phospholipase C, and IL-36α/γ was elevated only in pruritic psoriatic skin. This “itchscriptome” analysis will lead to an increased understanding of the molecular mechanisms of chronic pruritus and provide targets for itch treatment irrespective of disease state.

1-s2.0-S0022202X18300046-main

2019.04.05 Read More »

Journal Club 19.03.22.

WOOK-JOO LEE

Facilitation of MrgprD by TRP-A1 promotes neuropathic pain

Changming Wang,*,†,‡,§ Leying Gu,*,†,‡,§ Yonglan Ruan,*,†,‡,§ Xiao Geng,*,†,‡,§ Miao Xu,{ Niuniu Yang,*,k Lei Yu,*,† Yucui Jiang,*,† Chan Zhu,*,†,‡,§ Yan Yang,*,†,‡,§
Yuan Zhou,*,†,‡,§ Xiaowei Guan,*,†,‡,§ Wenqin Luo,# Qin Liu,**,††,‡‡ Xinzhong Dong,§§,{{ Guang Yu,*,†,‡,§,1 Lei Lan,{,2 and Zongxiang Tang*,†,‡,§
*School of Medicine and Life Sciences, †Key Laboratory of Chinese Medicine for Prevention and Treatment of Neurological Diseases, ‡State Key Laboratory Cultivation Base for Traditional Chinese Medicine Quality and Efficacy, and §Key Laboratory of Drug Target and Drug for Degenerative Disease of Jiangsu Province, Nanjing University of Chinese Medicine, Nanjing, China; {Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China; kDepartment of Traditional Chinese and Western Medicine, Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, China; #Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; **Department of Anesthesiology, ††Center for the Study of Itch, and ‡‡Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, USA; and §§The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, and {{Howard Hughes Medical Institute, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
ABSTRACT: Neuropathic pain remains a therapeutic challenge because of its complicated mechanisms. Mas-related GPCR D (MrgprD) is specifically expressed in small-diameter, nociceptive neurons of dorsal root ganglia (DRGs) and is implicated in pain modulation. However, the underlying mechanism of MrgprD involved in neuropathic pain remains elusive. In this study, we used behavioral experiments and physiologic examination methods to investigate the role of MrgprD in chronic constriction injury (CCI)–induced neuropathic pain. We found that MrgprD is necessary for the initiation of mechanical hypersensitivity and cold allodynia, but not for heat allodynia. Moreover, we demonstrated that transient receptor potential cation channel (TRP)-A1 was the ion channel down- stream of MrgprD, and the b-alanine–induced calcium signal was attributed mostly to TRP-A1 function. We further showed that PKA serves as a downstream mediator of b-alanine–activated MrgprD signaling to activate TRP-A1 in DRG neurons and in human embryonic kidney 293 cells, to coexpress MrgprD and TRP-A1 plasmids. Finally, we found that the b-alanine–induced pain behavior was increased, whereas the itching behavior was unchanged in CCI models compared with sham-injured animals. Knockout of TRPA1 also attenuated the b-alanine–induced pain behavior in CCI models. In conclusion, MrgprD is essential in cold allodynia in CCI-induced neuropathic pain through the PKA–TRP-A1 pathway. TRP-A1 facilitates MrgprD to development of neuropathic pain. Our findings reveal a novel mechanism of neuropathic pain formation and highlight MrgprD as a promising drug target for the treatment of neuropathic pain.—Wang, C., Gu, L., Ruan, Y., Geng, X., Xu, M., Yang, N., Yu, L., Jiang, Y., Zhu, C., Yang, Y., Zhou, Y., Guan, X., Luo, W., Liu, Q., Dong, X., Yu, G., Lan, L., Tang, Z. Facilitation of MrgprD by TRP-A1 promotes neuropathic pain. FASEB J. 33, 1360–1373 (2019). www.fasebj.org
KEY WORDS: MrgprA1 • dorsal root ganglia (DRG) • protein kinase A (PKA)

Journal Club 19.03.22. Read More »

2019.03.15

Babina Sanjel

Identification of a bilirubin receptor that may mediate a component of cholestatic itch.

Meixiong J^#¹, Vasavda C^#¹, Green D¹, Zheng Q¹, Qi L¹, Kwatra SG², Hamilton JP³, Snyder SH^1,^4,⁵,

Dong X^1,^2,^6,⁷.

Author information

Abstract

Various pathologic conditions result in jaundice, a yellowing of the skin due to a buildup of bilirubin. Patients with jaundice commonly report experiencing an intense non-histaminergic itch. Despite this association, the pruritogenic capacity of bilirubin itself has not been described, and no bilirubin receptor has been identified. Here, we demonstrate that pathophysiologic levels of bilirubin excite peripheral itch sensory neurons and elicit pruritus through MRGPRs, a family of G-protein coupled receptors expressed in primary sensory neurons. Bilirubin binds and activates two MRGPRs, mouse MRGPRA1 and human MRGPRX4. In two mouse models of pathologic hyperbilirubinemia, we show that genetic deletion of either Mrgpra1 or Blvra, the gene that encodes the bilirubin-producing enzyme biliverdin reductase, attenuates itch. Similarly, plasma isolated from hyperbilirubinemic patients evoked itch in wild-type animals but not Mrgpra1^-/- animals. Removing bilirubin decreased the pruritogenic capacity of patient plasma. Based on these data, targeting MRGPRs is a promising strategy for alleviating jaundice-associated itch.

KEYWORDS:

Mrgpr; bilirubin; cholestasis; itch; mouse; neuroscience; sensory neuron

Identification of a bilirubin receptor that may mediate a component of cholestatic itch

2019.03.15 Read More »

2019.03.08 journal club

qhsl93

12264_2017_Article_124

TNF-α/TNFR1 Signaling is Required for the Full Expression of Acute and Chronic Itch in Mice via Peripheral and Central Mechanisms.

Miao X¹, Huang Y², Liu TT², Guo R², Wang B², Wang XL³, Chen LH⁴, Zhou Y², Ji RR^5,⁶, Liu T^7,⁸.

Author information

Abstract

Increasing evidence suggests that cytokines and chemokines play crucial roles in chronic itch. In the present study, we evaluated the roles of tumor necrosis factor-alpha (TNF-α) and its receptors TNF receptor subtype-1 (TNFR1) and TNFR2 in acute and chronic itch in mice. Compared to wild-type (WT) mice, TNFR1-knockout (TNFR1-KO) and TNFR1/R2 double-KO (DKO), but not TNFR2-KO mice, exhibited reduced acute itch induced by compound 48/80 and chloroquine (CQ). Application of the TNF-synthesis inhibitor thalidomide and the TNF-α antagonist etanercept dose-dependently suppressed acute itch. Intradermal injection of TNF-α was not sufficient to evoke scratching, but potentiated itch induced by compound 48/80, but not CQ. In addition, compound 48/80 induced TNF-α mRNA expression in the skin, while CQ induced its expression in the dorsal root ganglia (DRG) and spinal cord. Furthermore, chronic itch induced by dry skin was reduced by administration of thalidomide and etanercept and in TNFR1/R2 DKO mice. Dry skin induced TNF-α expression in the skin, DRG, and spinal cord and TNFR1 expression only in the spinal cord. Thus, our findings suggest that TNF-α/TNFR1 signaling is required for the full expression of acute and chronic itch via peripheral and central mechanisms, and targeting TNFR1 may be beneficial for chronic itch treatment.

2019.03.08 journal club Read More »

181214 Osthole inhibits histamine dependent itch via modulating_YSH

Babina Sanjel

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4861971/pdf/srep25657.pdf

Osthole, an active coumarin isolated from Cnidium monnieri (L.) Cusson, has long been used in China as an antipruritic herbal medicine; however, the antipruitic mechanism of osthole is unknown. We studied the molecular mechanism of osthole in histamine-dependent itch by behavioral test, Ca²⁺ imaging, and electrophysiological experiments. First, osthole clearly remitted the scratching behaviors of mice induced with histamine, HTMT, and VUF8430. Second, in cultured dorsal root ganglion (DRG) neurons, osthole showed a dose-dependent inhibitory effect to histamine. On the same neurons, osthole also decreased the response to capsaicin and histamine. In further tests, the capsaicin-induced inward currents were inhibited by osthole. These results revealed that osthole inhibited histamine-dependent itch by modulating TRPV1 activity. This study will be helpful in understanding how osthole exerts anti-pruritus effects and suggests that osthole may be a useful treatment medicine for histamine-dependent itch.

Osthole inhibits histamine dependent itch via modulating

181214 Osthole inhibits histamine dependent itch via modulating_YSH Read More »

Matrine inhibits itching by lowering the activity of calcium channel

Babina Sanjel

Sophorae Flavescentis Radix (SFR) is a medicinal herb with many functions that are involved in antiinflammation, antinociception, and anticancer. SFR is also used to treat a variety of itching diseases. Matrine (MT) is one of the main constituents in SFR and also has the effect of relieving itching, but the antipruritic mechanism is still unclear. Here, we investigated the effect of MT on anti-pruritus. In acute and chronic itch models, MT significantly inhibited the scratching behavior not only in acute itching induced by histamine (His), chloroquine (CQ) and compound 48/80 with a dose-depended manner, but also in the chronic pruritus models of atopic dermatitis (AD) and acetone-ether-water (AEW) in mice. Furthermore, MT could be detected in the blood after intraperitoneal injection (i.p.) and subcutaneous injection (s.c.). Finally, electrophysiological and calcium imaging results showed that MT inhibited the excitatory synaptic transmission from dorsal root ganglion (DRG) to the dorsal horn of the spinal cord
by suppressing the presynaptic N-type calcium channel. Taken together, we believe that MT is a novel drug candidate in treating pruritus diseases, especially for histamine-independent and chronic pruritus, which might be attributed to inhibition of the presynaptic N-type calcium channel.

s41598-018-28661-x

https://www.nature.com/articles/s41598-018-28661-x

Matrine inhibits itching by lowering the activity of calcium channel Read More »

2018.09.21

Babina Sanjel

Oligomerization of MrgC11 and μ-opioid receptors in sensory neurons enhances morphine analgesia.

He SQ¹, Xu Q^2,³, Tiwari V¹, Yang F¹, Anderson M¹, Chen Z¹, Grenald SA¹, Raja SN¹, Dong X^4,³, Guan Y⁵.

Abstract

The μ-opioid receptor (MOR) agonist morphine is commonly used for pain management, but it has severe adverse effects and produces analgesic tolerance. Thus, alternative ways of stimulating MOR activity are needed. We found that MrgC11, a sensory neuron-specific G protein-coupled receptor, may form heteromeric complexes with MOR. Peptide-mediated activation of MrgC11 enhanced MOR recycling by inducing coendocytosis and sorting of MOR for membrane reinsertion. MrgC11 activation also inhibited the coupling of MOR to β-arrestin-2 and enhanced the morphine-dependent inhibition of cAMP production. Intrathecal coadministration of a low dose of an MrgC agonist potentiated acute morphine analgesia and reduced chronic morphine tolerance in wild-type mice but not in Mrg-cluster knockout (Mrg KO) mice. BAM22, a bivalent agonist of MrgC and opioid receptors, enhanced the interaction between MrgC11 and MOR and produced stronger analgesia than did the individual monovalent agonists. Morphine-induced neuronal and pain inhibition was reduced in Mrg KO mice compared to that in wild-type mice. Our results uncover MrgC11-MOR interactions that lead to positive functional modulation of MOR. MrgC shares genetic homogeneity and functional similarity with human MrgX1. Thus, harnessing this positive modulation of MOR function by Mrg signaling may enhance morphine analgesia in a sensory neuron-specific fashion to limit central side effects.

Oligomerization of MrgC11 and u-opioid receptors in sensory neurons enhances morphine analgesia.

Supplementary materials for -Oligomerization of MrgC11 and u-opioid receptors in sensory neurons enhances morphine analgesia.

2018.09.21 Read More »

IL-31 is crucial for induction of pruritus, but not inflammation, in contact hypersensitivity

Babina Sanjel

Abstract

IL-31, which is a member of the IL-6 family of cytokines, is produced mainly by activated CD4⁺ T cells, in particular activated Th2 cells, suggesting a contribution to development of type-2 immune responses. IL-31 was reported to be increased in specimens from patients with atopic dermatitis, and IL-31-transgenic mice develop atopic dermatitis-like skin inflammation, which is involved in the pathogenesis of atopic dermatitis. However, the role of IL-31 in development of contact dermatitis/contact hypersensitivity (CHS), which is mediated by hapten-specific T cells, including Th2 cells, is not fully understood. Therefore, we investigated this using IL-31-deficient (Il31^-/-) mice, which we newly generated. We demonstrated that the mice showed normal migration and maturation of skin dendritic cells and induction of hapten-specific T cells in the sensitization phase of FITC-induced CHS, and normal induction of local inflammation in the elicitation phase of FITC- and DNFB-induced CHS. On the other hand, those mice showed reduced scratching frequency and duration during FITC- and/or DNFB-induced CHS. Our findings suggest that IL-31 is responsible for pruritus, but not induction of local skin inflammation, during CHS induced by FITC and DNFB.

File below.

41598_2018_Article_25094

IL-31 is crucial for induction of pruritus, but not inflammation, in contact hypersensitivity Read More »