The role of Mrgpr signaling in the development of inflammation in atopic dermatitis

Mrgpr 信号在特应性皮炎炎症发展中的作用

• 批准号: 9919504
• 负责人: Sarina Berger Elmariah
• 金额: $ 17.3万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9919504
• 关键词: Adoptive Transfer; Allergic; Allergic Disease; Allergic inflammation; Antigens; Atopic Dermatitis; Attenuated; Automobile Driving; Behavior; Biosensor; Blood Vessels; Calcium; Cell Culture Techniques; Cell Degranulation; Cells; Chronic; Contact hypersensitivity; Cutaneous; Data; Development; Disease; Eczema; Event; Exposure to; Family; Fiber; G-Protein-Coupled Receptors; Goals; Hour; Human; IgE; Image; Imaging Techniques; Immune; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Innate Immune System; Mediating; Modeling; Molecular; Mus; Nerve; Nerve Block; Nerve Endings; Neurites; Neuroimmune; Neurons; Neuropeptides; Nociception; Ovalbumin; Pattern; Peptides; Peripheral; Pharmacology; Phase; Play; Precipitating Factors; Process; Proto-Oncogene Protein c-kit; Pruritus; Research; Role; Shapes; Signal Transduction; Skin; Small Interfering RNA; Spinal Ganglia; Stimulus; Substance P; TNF gene; Testing; Time; Up-Regulation; Work; afferent nerve; animal imaging; cytokine; detector; experimental study; formyl peptide; immunoregulation; in vivo; in vivo imaging; insight; knock-down; mast cell; member; mouse model; multimodality; nerve supply; pathogenic bacteria; prevent; public health relevance; receptor; recruit; relating to nervous system; response; scaffold; sensor; skin barrier; skin disorder; therapeutic target; tool; two-photon

 DESCRIPTION (provided by applicant): Atopic dermatitis (AD), commonly called `eczema', is a frequently disabling cutaneous disorder characterized by intense pruritus and chronic skin inflammation. Defective epidermal barrier function and immune dysregulation have long been considered the major precipitating factors in the development of AD. However, therapeutics targeting these factors alone are frequently inadequate to control atopic disease. Growing evidence from our lab and others suggests that peripheral sensory nerves play a critical role in modulating inflammatory responses in the skin. Performing in vivo imaging in a mouse model of chronic allergic eczema, I have shown that peripheral sensory nerves undergo neural pathfinding within days in response to epicutaneous exposure to ovalbumin. Neural proliferation and upregulation of neuropeptidergic fibers precede vascular reactivity and inflammatory influx by days to weeks. Pharmacologic blockade of neural activity during periods of OVA exposure prevents eczema development. These data suggest that peripheral sensory nerves act as biosensors to detect antigen(s) in the skin and subsequently to coordinate the vasoimmune response. Members of the Mas-related G- protein coupled receptor (Mrgpr) family function as innate sensors in a subset of cutaneous nociceptive fibers to relay non-histaminergic itch and in mast cells to mediate the stimulatory effects of inflammatory peptides resulting in mast cell degranulation. These neuronal and mast cell Mrgprs respond to a variety of endogenous and exogenous stimuli, making them attractive candidate molecules for serving dual functions of antigen surveillance and immune modulation in response to offending agents. I propose to use a multimodality approach including in vitro and in vivo strategies to evaluate the role of Mrgprs in mediating neural and mast cell responses to antigenic stimulation and in propagating of cutaneous inflammation in a mouse model of allergic eczema.

 描述（由申请人提供）：特应性皮炎（AD），通常称为“湿疹”，是一种常见的致残性皮肤疾病，其特征为剧烈瘙痒和慢性皮肤炎症。表皮屏障功能缺陷和免疫功能失调一直被认为是AD发生发展的主要促发因素。然而，单独针对这些因素的治疗通常不足以控制特应性疾病。来自我们实验室和其他实验室的越来越多的证据表明，外周感觉神经在调节皮肤炎症反应中起着关键作用。在慢性过敏性湿疹小鼠模型中进行体内成像，我已经表明，外周感觉神经在几天内进行神经寻路，以响应表皮暴露于卵清蛋白。神经增殖和神经肽能纤维的上调先于血管反应性和炎症流入数天至数周。在卵蛋白暴露期间，神经活动的药理学阻断可预防湿疹的发生。这些数据表明，外周感觉神经作为生物传感器检测皮肤中的抗原，并随后协调血管免疫反应。Mas相关的G蛋白偶联受体（Mrgpr）家族的成员在皮肤伤害感受纤维的子集中作为先天性传感器发挥作用以传递非组胺能性瘙痒，并且在肥大细胞中作为先天性传感器发挥作用以介导炎性肽的刺激作用，导致肥大细胞脱粒。这些神经元和肥大细胞Mrs11对各种内源性和外源性刺激作出响应，使它们成为有吸引力的候选分子，用于响应于攻击性试剂而提供抗原监视和免疫调节的双重功能。我建议使用一种多模态的方法，包括在体外和体内的策略，以评估的作用，Mrkaline在介导的神经和肥大细胞的抗原刺激反应，并在皮肤炎症的小鼠模型过敏性湿疹的传播。

项目成果

A prospective pilot study of narrowband UV-B treatment of lichen planopilaris.

窄带 UV-B 治疗扁平苔藓的前瞻性初步研究。

• DOI: 10.1016/j.jaad.2022.04.054
• 发表时间: 2022
• 期刊: Journal of the American Academy of Dermatology
• 影响因子: 13.8
• 作者: Pathoulas,JamesT;Flanagan,KellyE;Su,MackY;Elmariah,SarinaB;Zhan,Yao;Walker,ChloeJ;Burns,LauraJ;Manatis-Lornell,Athena;Penzi,Lauren;Miller,DanielD;Hordinsky,MariaK;Senna,MaryanneM
• 通讯作者: Senna,MaryanneM