Satellite Glial Cells and Neurons in Trigeminal Ganglia Are Altered in an Itch Model in Mice

MeytalCohen1,2, RachelFeldman-Goriachnik1,2 and MenachemHanani1,2,*

1 LaboratoryofExperimentalSurgery,Hadassah-HebrewUniversityMedicalCenter,Jerusalem91240,Israel; meytal.cohen@mail.huji.ac.il(M.C.);rahel.gor@gmail.com(R.F.-G.)

2 FacultyofMedicine,TheHebrewUniversityofJerusalem,MountScopus,Jerusalem91240,Israel * Correspondence:hananim@cc.huji.ac.il;Tel.:+972-2-5844721

Abstract: Itch(pruritus) is a common chronic condition with a lifetime prevalence of over 20%. The mechanisms underlying itch are poorly understood,and its therapy is difficult. There is recent evidence that following nerve injury or inflammation, intercellular communications in sensory ganglia are augmented, which may lead to abnormal neuronal activity, and hence to pain, but there is no information on whether such changes take place in an itch model. We studied changes in neurons and satellite glial cells(SGCs)in trigeminal ganglia in an itch model in mice using repeated applications of 2,4,6-trinitro-1-chlorobenzene(TNCB) to the external ear over a period of 11days. Treated mice showed augmented scratching behavior as compared with controls during the application period and for several days afterward.Immunostaining for the activation marker glial fibrillary acidic protein SGCs was greater by about 35% after TNCB application, and gap junction-mediated coupling between neurons increased from about 2% to 13%. The injection of gap junction blockers reduced scratching behavior, suggesting that gap junctions contribute to itch. Calcium imaging studies showed increased responses of SGCs to the pain (and presumed itch )mediator ATP. We conclude that changes in both neurons and SGCs in sensory ganglia may play a role in itch.

Pamoic Acid-Induced Peripheral GPR35 Activation Improves Pruritus and Dermatitis

Chaeeun Kim ¹, Yerin Kim ¹, Ji Yeon Lim ¹, Minseok Kim ¹, Haiyan Zheng ¹, Miri Kim ¹, Sun Wook Hwang ¹

Affiliations expand

• PMID: 37501600
• DOI: 10.1111/bph.16201

Abstract

Background and purpose: Pruritic dermatitis is a disease with a considerable unmet need for treatment and appears to present with not only epidermal but also peripheral neuronal complications. Here we propose a novel pharmacologic modulation targeting both peripheral dorsal root ganglion (DRG) sensory neurons and skin keratinocytes. GPR35 is an orphan G-protein-coupled receptor expressed in DRG neurons and has been predicted to downregulate neuronal excitability when activated. Modulator information is currently increasing for GPR35 and pamoic acid (PA), a salt-forming agent for drugs, has been shown to be an activator solely specific for GPR35. Here we investigated its effect on dermatitic pathology.

Experimental approach: We confirmed GPR35 expression in peripheral neurons and tissues. The effect of PA treatment was pharmacologically evaluated in cultured cells in vitro and in in vivo animal models for acute and chronic pruritus.

Key results: Local PA application mitigated acute non-histaminergic itch and consistently, obstructed DRG neuronal responses. Keratinocyte fragmentation under dermatitic simulation was also dampened following PA incubation. Chronic pruritus in 1-chloro-2,4-dinitrobenzene (DNCB) and psoriasis models was also moderately but significantly reversed by the repeated applications of PA. Dermatitic scores in the DNCB and psoriatic models were also improved by its application, indicating that it is beneficial for mitigating disease pathology.

Conclusions and implications: Our findings suggest that pamoic acid activation of peripheral GPR35 can contribute to the improvement of pruritus and its associated diseases.

Keywords: GPR35; Pamoic acid; dermatitis; itch; neuron.

Eun Ju Kim ^abc, Dong Hun Lee ^abc, Yeon Kyung Kim ^abc, Min-Kyoung Kim ^abc, Jung Yun Kim ^abc, Min Jung Lee ^abc, Won Woo Choi ^abc, Hee Chul Eun ^abc, Jin Ho Chung ^abc

Summary

Background

Sensitive skin represents hyperactive sensory symptoms showing exaggerated reactions in response to internal stimulants or external irritants. Although sensitive skin is a very common condition affecting an estimated 50% of the population, its pathophysiology remains largely elusive, particularly with regard to its metabolic aspects.

Objective

The objective of our study was to investigate the pathogenesis of sensitive skin.

Methods

We recruited healthy participants with ‘sensitive’ or ‘non-sensitive’ skin based on standardized questionnaires and 10% lactic acid stinging test, and obtained skin samples for microarray analysis and subsequent experiments.

Results

Microarray transcriptome profiling revealed that genes involved in muscle contraction, carbohydrate and lipid metabolism, and ion transport and balance were significantly decreased in sensitive skin. These altered genes could account for the abnormal muscle contraction, decreased ATP amount in sensitive skin. In addition, pain-related transcripts such as TRPV1, ASIC3 and CGRP were significantly up-regulated in sensitive skin, compared with non-sensitive skin.

Conclusions

Our findings suggest that sensitive skin is closely associated with the dysfunction of muscle contraction and metabolic homeostasis.

Cell Immunol 2021 Oct;368:104422. doi: 10.1016/j.cellimm.2021.104422. Epub 2021 Aug 8.

Meesum Syed ¹, Ananth K Kammala ¹, Brianna Callahan ¹, Carole A Oskeritzian ², Hariharan Subramanian ³Affiliations expand

• PMID: 34399172
• PMCID: PMC8428143
• DOI: 10.1016/j.cellimm.2021.104422

Abstract

MAS related G-protein coupled receptor X2 (MRGPRX2) is a G-protein coupled receptor (GPCR) expressed in human mast cells that has been implicated to play an important role in causing pseudo-allergic reactions as well as exacerbating inflammation during asthma and other allergic diseases. Lactic acid, a byproduct of glucose metabolism, is abundantly present in inflamed tissues and has been shown to regulate functions of several immune cells. Because the endogenous ligands for MRGPRX2 (substance P and LL-37) are elevated during pathologic conditions, such as cancer and asthma, and given that lactic acid levels are also enhanced in these patients, we explored the role of lactic acid in regulating mast cells response via MRGPRX2 and MrgprB2, the mouse orthologue of the human receptor. We found that lactic acid suppressed both the early (Ca²⁺ mobilization and degranulation) and late (chemokine/cytokine release) phases of mast cell activation; this data was confirmed in LAD2, human skin and mouse peritoneal mast cells. In LAD2 cells, the reduction in degranulation and chemokine/cytokine production mediated by lactic acid was dependent on pH. In agreement with our in vitro studies, lactic acid also reduced passive systemic anaphylaxis to compound 48/80 (a known MRGPRX2/MrgprB2 ligand) and skin inflammation in a mouse model of rosacea that is dependent on MrgprB2 expression on skin mast cells. Our data thus suggest that lactic acid may serve to inhibit mast cell-mediated inflammation during asthma and reduce immune response during cancer by affecting mast cell activation through MRGPRX2.

Keywords: Lactic acid; MAS-related G-protein coupled receptor-X2 (MRGPRX2); Mast cells; MrgprB2; Pseudo-allergic reactions.

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