Modulation of Chronic Th2 inflammation by the CCR8 Receptor-Ligand Pathway

CCR8 受体-配体途径对慢性 Th2 炎症的调节

• 批准号: 9239296
• 负责人: SABINA A ISLAM
• 金额: $ 41.69万
• 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: 2016-11-21 至 2021-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9239296
• 关键词: Acute; Address; Adipose tissue; Agonist; Allergens; Allergic; Allergic Disease; Allergic inflammation; Anti-Inflammatory Agents; Anti-inflammatory; Antigen-Antibody Complex; Atopic Dermatitis; Binding; CCL18 gene; CCR8 gene; Cells; Chronic; Chronic Phase; Clinical; Data; Development; Disease; Eczema; Employee Strikes; Eosinophilia; Epithelial; Extrinsic asthma; Flare; Generations; Genes; Genetic; Goals; Health Care Costs; Human; Immune; Immunosuppressive Agents; Individual; Inflammation; Inflammatory; Innate Immune System; Interleukin-10; Interleukin-13; Interleukin-5; Knowledge; Lead; Lesion; Leukocyte Trafficking; Leukocytes; Ligands; Lymphoid Cell; Mediating; Mediator of activation protein; Modeling; Morbidity - disease rate; Mus; Natural Immunity; Pathogenicity; Pathology; Pathway interactions; Patients; Phase; Phenotype; Preventive Intervention; Productivity; Publishing; Recruitment Activity; Recurrence; Refractory; Signal Transduction; Skin; Specimen; Steroids; Stimulus; Suggestion; TSLP gene; Testing; Therapeutic Intervention; Tissues; Work; adaptive immunity; analog; autocrine; chemokine; chemokine receptor; cytokine; eosinophil; eosinophilic inflammation; genetic signature; human disease; in vivo; innovation; insight; macrophage; new therapeutic target; novel; programs; receptor; response; trafficking; transcriptome

Summary Regulators of Th2 inflammation at the barrier interface in chronic allergic diseases such as atopic dermatitis and asthma are not as well characterized as those in the initiation phase. Yet effector functions of leukocytes in the chronic phase of Th2 inflammation drive symptomatic human disease that results in immune pathology associated with much morbidity after usually asymptomatic allergen sensitization. Chemokines are chemotactic cytokines that control leukocyte recruitment and inflammation by binding specific receptors on target cells. We recently discovered that the human chemokine CCL18 is a novel agonist of the CCR8 receptor. CCL18 is a signature chemokine produced by Th2 cytokine differentiated IL-4 spectrum macrophages, M(IL-4)s, also known as alternatively activated or M2 macrophages. CCL18 is associated with several chronic and eosinophilic inflammatory human diseases, and is one of the most highly induced chemokines in lesional atopic dermatitis skin. M(IL-4) interactions with the recently discovered Group 2 Innate Lymphoid Cells (ILC2) have been shown to facilitate eosinophilic inflammation. CCR8 is also a top signature gene of the mouse ILC2 transcriptome. Recently IL-4Rα blockade, which inhibits M(IL-4) differentiation, resulted in striking clinical improvement of treatment refractory atopic dermatitis that highly correlated with suppression of CCL18. Yet, whether and how CCL18 and M(IL-4)s sustain chronic atopic dermatitis pathology is not known. Our published and new preliminary data lead us to hypothesize that though M(IL-4)s are anti-inflammatory in acute inflammation, they undergo pathogenic transformation at barrier interfaces to become pro-inflammatory in chronic inflammation, and partly through the CCR8 pathway and other mediators, and local interactions with cells such as ILC2s sustain chronic eosinophilic allergic inflammation in the skin. To test this hypothesis we will use a model of chronic allergic dermatitis. We also discovered a novel mouse chemokine agonist of the CCR8 receptor that is a functional analog of CCL18. We thus propose to: (1) Determine if M(IL-4)s are crucial for chronic allergic inflammation and identify mechanisms by which they do so, and if this is regulated by the CCR8 pathway; and (2) Define how ILC2s contribute to chronic allergic inflammation and if this is mediated by the CCR8 pathway. We will determine the clinical correlates of the studies proposed in Aims 1 and 2 using clinical specimens from individuals with eczema that will be compared to healthy controls.

概括 慢性过敏性疾病（例如特应性）的屏障接口处Th2注射的调节剂 皮肤炎和哮喘的特征不如启动阶段的特征。效应子功能 在Th2炎症驱动有症状的人类疾病的慢性阶段白细胞的疾病中 通常无症状过敏原感应后，与多重发病率相关的免疫病理学。 趋化因子是趋化细胞因子，通过结合控制白细胞募集和炎症 靶细胞上的特定受体。我们最近发现人类趋化因子CCL18是一种新颖 CCL18是由Th2细胞因子分化产生的签名趋化因子 IL-4光谱巨噬细胞M（IL-4）S，也称为替代激活或M2巨噬细胞。 CCL18与几种慢性和嗜酸性炎性人类疾病有关，并且是 病变特应性皮肤炎皮肤中最高度诱导的趋化因子。 M（IL-4）与 最近发现的2组先天淋巴样细胞（ILC2）已显示可促进嗜酸性粒细胞 炎。 CCR8也是小鼠ILC2转录组的顶级签名基因。最近IL-4Rα 抑制M（IL-4）分化的封锁导致治疗的临床改善 与CCL18抑制高度相关的难治性性皮炎。但是，是否以及如何 CCL18和M（IL-4）的持续慢性特应性皮炎病理尚不清楚。我们出版的新 初步数据导致我们假设M（IL-4）在急性炎症中具有抗炎，但 他们在屏障界面处经历致病性转化，以在慢性 炎症，部分通过CCR8途径和其他介体，以及与细胞的局部相互作用 例如ILC2S在皮肤中维持慢性嗜酸性过敏性注射。为了检验这个假设，我们将 使用慢性过敏性皮炎的模型。我们还发现了一种新型的小鼠趋化因子激动剂 CCR8受体是CCL18的功能类似物。因此，我们建议：（1）确定m（il-4）是否为 对于慢性过敏性注射至关重要，并确定了这样做的机制，如果是这样 由CCR8途径调节； （2）定义ILC2如何促进慢性过敏性注射和 如果这是由CCR8途径介导的。我们将确定提出的研究的临床相关性 在AIMS 1和2中，使用湿疹个体的临床标本将与健康进行比较 控件。