MrgprB4 in trigeminal neurons expressing TRPA1 modulates unpleasant sensations

Shota Tobori a, 1, Haruka Hiyama a, 1, Takahito Miyake a, b, Yuichi Yano a, Kazuki Nagayasu a, Hisashi Shirakawa a, *, Takayuki Nakagawa c, Yasuo Mori d, Shuji Kaneko a

a Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan
b Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto 606- 8501, Japan

c Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, 54 Shogoin -Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
d Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Building A4, Katsura Campus, Nishikyo-ku, Kyoto 615-8510, Japan

ABSTRACT

Gentle touch such as stroking of the skin produces a pleasant feeling, which is detected by a rare subset of sensory neurons that express Mas-related G protein-coupled receptor B4 (MrgprB4) in mice. We examined small populations of MrgprB4-positive neurons in the trigeminal ganglion and the dorsal root ganglion, and most of these were sensitive to transient receptor potential ankyrin 1 (TRPA1) agonist but not TRPV1, TRPM8, or TRPV4 agonists. Deficiency of MrgprB4 did not affect noxious pain or itch be- haviors in the hairless plantar and hairy cheek. Although behavior related to acetone-induced cold sensing in the hind paw was not changed, unpleasant sensory behaviors in response to acetone appli- cation or sucrose splash to the cheek were significantly enhanced in Mrgprb4-knockout mice as well as in TRPA1-knockout mice. These results suggest that MrgprB4 in the trigeminal neurons produces pleasant sensations in cooperation with TRPA1, rather than noxious or cold sensations. Pleasant sensa- tions may modulate unpleasant sensations on the cheek via MrgprB4.

© 2021 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Keywords:

Sensory behavior Hairy skin
MrgprB4
TRPA1
Trigeminal ganglion

Hierarchical Specification of Pruriceptors by Runt-Domain Transcription Factor Runx1

Lu Qi, Chengcheng Huang, Xiaohua Wu, Yeqi Tao, Jingjing Yan, Tianyong Shi, Cheng Cao, Lu Han, Mengsheng Qiu, Qiufu Ma, Zijing Liu , Yang Liu 

The Journal of Neuroscience, May 31, 2017

Abstract

The somatic sensory neurons in dorsal root ganglia (DRG) detect and transmit a diverse array of sensory modalities, such as pain, itch, cold, warm, touch, and others. Recent genetic and single-cell RNA sequencing studies have revealed a group of DRG neurons that could be particularly relevant for acute and chronic itch information transmission. They express the natriuretic peptide type B (NPPB), as well as a cohort of receptors and neuropeptides that have been implicated in chronic itch manifestation, including the interleukin-31 receptor A (IL-31ra) and its coreceptor oncostatin M receptor (Osmr), the cysteinyl leukotriene receptor 2 (Cysltr2), somatostatin, and neurotensin. However, how these neurons are generated during development remains unclear. Here we report that Runx1 is required to establish all these molecular features of NPPB⁺ neurons. We further show that while early embryonic Runx1 activity is required for the formation of NPPB⁺ cells, at later stages Runx1 switches to a genetic repressor and thus its downregulation becomes a prerequisite for the proper development of these pruriceptors. This mode by Runx1 is analogous to that in controlling another group of pruriceptors that specifically express the chloroquine receptor MrgprA3. Finally, behavioral studies using both sexes of mice revealed marked deficits in processing acute and chronic itch in Runx1 conditional knock-out mice, possibly attributable to impaired development of various pruriceptors.

SIGNIFICANCE STATEMENT 

Our studies reveal a generalized control mode by Runx1 for pruriceptor development and consolidate a hierarchical control mechanism for the formation of sensory neurons transmitting distinct modalities. Among dorsal root ganglion neurons that initially express the neurotrophin receptor TrkA, Runx1 is necessary for the proper development of those neurons that innervate tissues derived from the ectoderm such as skin epidermis and hair follicles. These Runx1-dependent cutaneous sensory neurons are then divided into two groups based on persistent or transient Runx1 expression. The Runx1-persistent group is involved in transmitting mechanical and thermal information, whereas the Runx1-transient group transmits pruriceptive information. Such hierarchical control mechanisms may provide a developmental solution for the formation of sensory circuits that transmit distinct modalities.

Keywords: NPPB; Runx1; chronic itch; development; pruriceptor; transcriptional regulation.

Cimifugin relieves pruritus in psoriasis by inhibiting TRPV4

Published in:- Cell Calcium

JinjinYan^aFanYe^aYingJu^aDijunWang^aJiaoChen^bcXinyuZhang^aZhiYin^dChangmingWang^aYanYang^aChanZhu^aYuanZhou^aPengCao^bcYangXu^dGuangYu^aZongxiangTang^a

DOI: https://doi.org/10.1016/j.ceca.2021.102429

Psoriasis is an immune-mediated chronic inflammatory skin disease characterized by erythema, scales, and infiltration of the skin, which causes deleterious effects on patient quality of life. TRP channel played important roles in the generation and conductance of itch signal . According to our results, psoriasis induced itch was TRPV4 dependent, and TRPV4 expression in both epidermis and DRG were up-regulated in psoriasis. Thus, TRPV4 is an attractive candidate for treating psoriasis induced itch. Cimifugin is a common compound in antipruritic Chinese medicine. In our study, GSK1016790A, a TRPV4 channel specific agonist, induced acute itch was inhibited by cimifugin in a dose-dependent manner. Furthermore, cimifugin treatment reduced the scratching behavior and reversed the TRPV4 up-regulation induced by psoriasis. In particular, cimifugin decreased GSK1016790A induced calcium response both in HaCaT cells and DRG neurons. Importantly, in TRPV4 transfected HEK293 cells, GSK101 induced calcium response was also significantly inhibited by cimifugin pretreatment. Consistent with our calcium imaging result, cimifugin pretreatment also inhibited GSK101 induced inward currents. Our study delineated a new role of TRPV4 in psoriasis and emphasized the antipruritic effect of cimifugin, which opened a new avenue to itch management in psoriasis.

Keyword: Psoriasis, Trpv4, Itch, Cimifugin

MrgprC11+ sensory neurons mediate glabrous skin itch

Proc Natl Acad Sci U S A. 2021 Apr 13;118(15):e2022874118. doi: 10.1073/pnas.2022874118.

Haley R. Steele, Yanyan Xinga, Yuyan Zhu, Henry B. Hilley, Katy Lawson, Yeseul Nho, Taylor Niehoff, and Liang Hana

School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30332
Edited by Jeremy Nathans, Johns Hopkins University School of Medicine, Baltimore, MD, and approved March 2, 2021 (received for review November 2, 2020)

Itch arising from glabrous skin (palms and soles) has attracted limited attention within the field due to the lack of methodology. This is despite glabrous itch arising from many medical conditions such as plantar and palmar psoriasis, dyshidrosis, and cholestasis. Therefore, we developed a mouse glabrous skin behavioral assay to investigate the contribution of three previously identified pruriceptive neurons in glabrous skin itch. Our results show that MrgprA3+ and MrgprD+ neurons, although key mediators for hairy skin itch, do not play important roles in glabrous skin itch, dem- onstrating a mechanistic difference in itch sensation between hairy and glabrous skin. We found that MrgprC11+ neurons are the major mediators for glabrous skin itch. Activation of MrgprC11+ neurons induced glabrous skin itch, while ablation of MrgprC11+ neurons reduced both acute and chronic glabrous skin itch. Our study provides insights into the mechanisms of itch and opens up new avenues for future glabrous skin itch research.

Runx1 Determines Nociceptive Sensory Neuron Phenotype and Is Required for Thermal and Neuropathic Pain

Chih-Li Chen, Daniel C Broom, Yang Liu, Joriene C de Nooij, Zhe Li, Chuan Cen, Omar Abdel Samad, Thomas M Jessell, Clifford J Woolf, Qiufu Ma

Abstract

In mammals, the perception of pain is initiated by the transduction of noxious stimuli through specialized ion channels and receptors expressed by nociceptive sensory neurons. The molecular mechanisms responsible for the specification of distinct sensory modality are, however, largely unknown. We show here that Runx1, a Runt domain transcription factor, is expressed in most nociceptors during embryonic development but in adult mice, becomes restricted to nociceptors marked by expression of the neurotrophin receptor Ret. In these neurons, Runx1 regulates the expression of many ion channels and receptors, including TRP class thermal receptors, Na+-gated, ATP-gated, and H+-gated channels, the opioid receptor MOR, and Mrgpr class G protein coupled receptors. Runx1 also controls the lamina-specific innervation pattern of nociceptive afferents in the spinal cord. Moreover, mice lacking Runx1 exhibit specific defects in thermal and neuropathic pain. Thus, Runx1 coordinates the phenotype of a large cohort of nociceptors, a finding with implications for pain therapy.

Nat Commun 2021 Apr 12;12(1):2185. doi: 10.1038/s41467-021-22479-4.

Therapeutic B-cell depletion reverses progression of Alzheimer’s disease

Ki Kim ^# 1, Xin Wang ^# 1, Emeline Ragonnaud ^# 1, Monica Bodogai ^# 1, Tomer Illouz ^2 3 4, Marisa DeLuca ¹, Ross A McDevitt ⁵, Fedor Gusev ⁶, Eitan Okun ^2 3 4, Evgeny Rogaev ^6 7 8 9, Arya Biragyn ¹⁰

• PMID: 33846335
• PMCID: PMC8042032
• DOI: 10.1038/s41467-021-22479-4

Abstract

The function of B cells in Alzheimer’s disease (AD) is not fully understood. While immunoglobulins that target amyloid beta (Aβ) may interfere with plaque formation and hence progression of the disease, B cells may contribute beyond merely producing immunoglobulins. Here we show that AD is associated with accumulation of activated B cells in circulation, and with infiltration of B cells into the brain parenchyma, resulting in immunoglobulin deposits around Aβ plaques. Using three different murine transgenic models, we provide counterintuitive evidence that the AD progression requires B cells. Despite expression of the AD-fostering transgenes, the loss of B cells alone is sufficient to reduce Aβ plaque burden and disease-associated microglia. It reverses behavioral and memory deficits and restores TGFβ⁺ microglia, respectively. Moreover, therapeutic depletion of B cells at the onset of the disease retards AD progression in mice, suggesting that targeting B cells may also benefit AD patients.

Nat Commun. 2020 Dec 11;11(1):6363. doi: 10.1038/s41467-020-19931-2.

Effect of gut microbiota on depressive-like behaviors in mice is mediated by the endocannabinoid system

Grégoire Chevalier ¹, Eleni Siopi ², Laure Guenin-Macé ³, Maud Pascal ^1 2, Thomas Laval ³, Aline Rifflet ⁴, Ivo Gomperts Boneca ⁴, Caroline Demangel ³, Benoit Colsch ⁵, Alain Pruvost ⁵, Emeline Chu-Van ⁵, Aurélie Messager ⁵, François Leulier ⁶, Gabriel Lepousez ², Gérard Eberl ⁷, Pierre-Marie Lledo ⁸

• PMID: 33311466
• PMCID: PMC7732982
• DOI: 10.1038/s41467-020-19931-2

Abstract

Depression is the leading cause of disability worldwide. Recent observations have revealed an association between mood disorders and alterations of the intestinal microbiota. Here, using unpredictable chronic mild stress (UCMS) as a mouse model of depression, we show that UCMS mice display phenotypic alterations, which could be transferred from UCMS donors to naïve recipient mice by fecal microbiota transplantation. The cellular and behavioral alterations observed in recipient mice were accompanied by a decrease in the endocannabinoid (eCB) signaling due to lower peripheral levels of fatty acid precursors of eCB ligands. The adverse effects of UCMS-transferred microbiota were alleviated by selectively enhancing the central eCB or by complementation with a strain of the Lactobacilli genus. Our findings provide a mechanistic scenario for how chronic stress, diet and gut microbiota generate a pathological feed-forward loop that contributes to despair behavior via the central eCB system.

 Br J Dermatol. 2018 Sep;179(3):669-678. doi: 10.1111/bjd.16498.Epub 2018 Jun 21.

Itch in dermatomyositis: the role of increased skin interleukin-31

H J Kim ^1 2 3, M Zeidi ^1 2, D Bonciani ^1 2 4, S M Pena ², J Tiao ^1 2, S Sahu ^1 2, V P Werth ^1 2

• PMID: 29494763
• PMCID: PMC6119520
• DOI: 10.1111/bjd.16498

Abstract

Background: Interleukin (IL)-31 is implicated in pruritus associated with pruritic skin diseases like atopic dermatitis. Although pruritus is a prominent feature in dermatomyositis (DM), few studies have evaluated the pathogenesis of DM-associated itch.

Objectives: To establish the prevalence of itch in DM, and to investigate the role of IL-31 in DM-related itch.

Methods: Pruritus and disease activity of DM were evaluated by a visual analogue scale (VAS) and the Cutaneous Disease and Activity Severity Index (CDASI), respectively. Expression of IL-31 and IL-31 receptor alpha (IL-31RA) in lesional DM, nonlesional DM and healthy control skin was evaluated by quantitative reverse-transcriptase polymerase chain reaction and immunofluorescence. Flow cytometry was performed on skin cells isolated from lesional DM skin to identify cellular sources of IL-31 in DM.

Results: Among 191 patients with DM, 50·8% had moderate-to-severe itch, and itch was correlated with increased cutaneous severity (r = 0·34). In patients with itchy DM, gene expression of IL31 and IL31RA in lesional skin was upregulated compared with nonlesional skin and healthy control skin. IL31 mRNA expression positively correlated with VAS itch score (r = 0·67). On immunofluorescence, immunoreactivity for IL-31 and IL-31RA was stronger in lesional skin. Flow cytometry showed that lesional DM skin contained significantly more IL-31-producing cells, and CD4⁺ cells were the most common cell type. Lenabasum, an emerging treatment for DM, significantly downregulated IL-31 from CpG-stimulated peripheral blood mononuclear cells.

Conclusions: Increased skin IL-31 may play a role in DM-associated itch, and ongoing trials will evaluate the effects of systemic treatment on IL-31 and itch in DM.

J Invest Dermatol. 2021 Apr 1;S0022-202X(21)01129-5. doi: 10.1016/j.jid.2021.03.015.Online ahead of print.

Mechanisms of broad-band ultraviolet B irradiation-induced itch in mice

Liang Cao ¹, Xueping Yue ¹, Yonghui Zhao ¹, Lixia Du ¹, Zili Xie ¹, Yi Yuan ¹, Sha Zhang ², Feng Li ², Jing Feng ³, Hongzhen Hu ¹

• PMID: 33812858
• DOI: 10.1016/j.jid.2021.03.015

Abstract

Although sunburn can produce severe uncontrollable itching, the underlying mechanisms of ultraviolet (UV) irradiation-induced itch are poorly understood because of a lack of experimental animal models of sunburn itch. Here we established a sunburn-related mouse model and found that Broad-band UVB (BB-UVB) irradiation elicited scratching but not wiping behavior in mice. By using a combination of live-cell Ca²⁺ imaging and quantitative RT-PCR on dorsal root ganglion (DRG) neurons, hematoxylin and eosin staining, immunofluorescence staining of skin preparations, behavioral testing, in combination with genetic and pharmacological approaches, we showed that TRPV1-positive DRG neurons but not mast cells are involved in BB-UVB irradiation-induced itch. Moreover, both genetic and pharmacological inhibition of TRPV1 function significantly alleviated BB-UVB irradiation-induced itch response. Collectively, our results suggest that BB-UVB irradiation evokes itch sensation in mice through promoting TRPV1 channel function in DRG neurons and provide potential therapeutic targets for sunburn-related itch.

Keywords: BB-UVB; Itch model; Sunburn-related itch; TRPV1.

Astrocytic STAT3 activation and chronic itch require IP3R1/TRPC-dependent Ca21 signals in mice

Miho Shiratori-Hayashi, PhD,a Chiharu Yamaguchi, MPharm,a Kazushi Eguchi, MPharm,a Yuto Shiraishi, BPharm,a Keita Kohno, BPharm,a Katsuhiko Mikoshiba, MD, PhD,b,c,d Kazuhide Inoue, PhD,e Motohiro Nishida, PhD,f,g and Makoto Tsuda, PhDa 

Background: Chronic itch is a debilitating symptom of inflammatory skin diseases, but the underlying mechanism is poorly understood. We have recently demonstrated that astrocytes in the spinal dorsal horn become reactive in models of atopic and contact dermatitis via activation of the transcription factor signal transducer and activator of transcription 3 (STAT3) and critically contribute to chronic itch. In general, STAT3 is transiently activated; however, STAT3 activation in reactive astrocytes of chronic itch model mice persistently occurs via an unknown mechanism.
Objective: We aimed to determine the mechanisms of persistent activation of astrocytic STAT3 in chronic itch conditions. Methods: To determine the factors that are required for persistent activation of astrocytic STAT3, Western blotting and calcium imaging with cultured astrocytes or spinal cord slices were performed. Thereafter, chronic itch model mice were used for genetic and behavioral experiments to confirm the role of the factors determined to mediate persistent STAT3 activation from in vitro and ex vivo experiments in chronic itch.

Results: IP3 receptor type 1 (IP3R1) knockdown in astrocytes suppressed IL-6–induced persistent STAT3 activation and expression of lipocalin-2 (LCN2), an astrocytic STAT3- dependent inflammatory factor that is required for chronic itch. IP3R1-dependent astrocytic Ca21 responses involved Ca21 influx through the cation channel transient receptor potential canonical (TRPC), which was required for persistent STAT3 activation evoked by IL-6. IL-6 expression was upregulated in dorsal root ganglion neurons in a mouse model of chronic itch. Dorsal root ganglion neuron–specific IL-6 knockdown, spinal astrocyte–specific IP3R1 knockdown, and pharmacologic spinal TRPC inhibition attenuated LCN2 expression and chronic itch.

Conclusion: Our findings suggest that IP3R1/TRPC channel– mediated Ca21 signals elicited by IL-6 in astrocytes are necessary for persistent STAT3 activation, LCN2 expression, and chronic itch, and they may also provide new targets for therapeutic intervention. (J Allergy Clin Immunol 2021;147:1341-53.)

Key words: Contact dermatitis, chronic itch, astrocytes, STAT3, lip- ocalin-2, Ca21 signal, IP3R1, TRPC, IL-6, primary afferent sensory neuron