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

基本信息

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
项目类别：
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

项目摘要

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.

概括特应性等慢性过敏性疾病屏障界面 Th2 炎症的调节因子皮炎和哮喘的特征并不像起始阶段那样明确。 Th2 炎症慢性期的白细胞数量会驱动有症状的人类疾病，从而导致免疫病理学与通常无症状的过敏原致敏后的许多发病率相关。趋化因子是趋化细胞因子，通过结合来控制白细胞的募集和炎症。我们最近发现人类趋化因子 CCL18 是一种新型趋化因子。 CCR8 受体激动剂是由 Th2 细胞因子分化产生的标志性趋化因子。 IL-4 谱巨噬细胞，M(IL-4)，也称为替代激活巨噬细胞或 M2 巨噬细胞。 CCL18 与多种慢性和嗜酸性粒细胞炎症性人类疾病有关，是其中之一皮损特应性皮炎皮肤中最高度诱导的趋化因子 M(IL-4) 与最近发现的第 2 组先天淋巴细胞 (ILC2) 已被证明可以促进嗜酸性粒细胞最近，CCR8 也是小鼠 ILC2 转录组的顶级标志基因。阻断可抑制 M(IL-4) 分化，导致临床治疗效果显着改善难治性特应性皮炎与 CCL18 的抑制高度相关然而，是否以及如何。 CCL18 和 M(IL-4) 维持慢性特应性皮炎的病理学尚不清楚。初步数据表明，尽管 M(IL-4) 在急性炎症中具有抗炎作用，它们在屏障界面处经历致病性转化，在慢性病中变得促炎。炎症，部分通过 CCR8 通路和其他介质，以及与细胞的局部相互作用例如 ILC2 维持皮肤中的慢性嗜酸性过敏性炎症。为了检验这一假设，我们将进行测试。使用慢性过敏性皮炎模型我们还发现了一种新型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) 是否是。对于慢性过敏性炎症至关重要，并确定其作用机制，如果这是受 CCR8 通路调节；(2) 定义 ILC2 如何促进慢性过敏性炎症；如果这是由 CCR8 途径介导的，我们将确定所提出的研究的临床相关性。在目标 1 和 2 中，使用湿疹患者的临床标本与健康人进行比较控制。